Pulmoner Emboli

PHYSIOLOGICAL REVIEWS
Vol. 63, No. 3, July 1983

Printed in USA.
Pulmonary Microembolism
ASRAR B. MALIK
Department of Ph@oZogg,Albany MidicuZ College
of Union University, Albany, New York
I. Introduction ......................................................... 1115
A. Recent reviews ................................................... 1115
B. Pulmonary microembolism and thrombogenesis .................... 1115
C. Methods of producing pulmonary microembolism ................... 1116
II. Pulmonary Hemodynamic Response to Microembolization .............. 1117
A. Mechanisms of increase in pulmonary vascular resistance ........... 1117
B. Factors mediating pulmonary vasoconstriction ..................... 1120
III. Pulmonary Edema After Microembolization ............................ 1127
A. Effects of pulmonary microembolism on lung fluid balance .......... 112’7
B. Effects of increasing degree of embolization ........................ 1132
C. Reversibility of increases in permeability ....................... .... 1134
D. Morphological alterations in lung endothelium ..................... 1136
E. Microvessels versus arteries as sites of fluid and protein exchange ... 1138
F. Hemodynamic mechanisms associated with increased permeability .. 1139
G. Lymphatic impairment ............................................ 1140
H. Effects of regional atelectasis ...................................... 1141
I. Cellular and humoral mechanisms ................................. 1141
J. Ischemia ......................................................... 1166
K. Neural factors .................................................... 1166
L. Role of bronchial circulation ...................................... 116’7
M. Cellular edema ................................................... 1167
IV. Tachypnea After Microembolization ................................... 1169
A. Lung irritant or rapidly adapting receptors ........................ 1170
B. Juxtapulmonary capillary receptors (C fibers) ...................... 1170
C. Pulmonary arterial baroreceptors .................................. 1172
D. Pulmonary stretch receptors ...................................... 1173
E. Summary ........................................................ 1173
V. Airway Constriction After Microembolization .......................... 1174
A. Sites of bronchoconstriction ....................................... 1174
B. Factors affecting bronchoconstriction .............................. 1175
C. Mechanisms involved in producing bronchoconstriction ............. 1176
D. Homeostatic value of bronchoconstriction .......................... 1178
E. Alveolar dead space after embolization ............................. 1179
F. Alveolar collapse ................................................. 1179
VI. Mechanisms of Arterial Hypoxia ...................................... 1180
A. Time course of gas-exchange impairment ........................... 1180
B. Diffusion impairment ............................................. 1181
C. Increased venous admixture ....................................... 1181
D. Ventilation-perfusion imbalance ................................... 1182
E. Alveolar hypoventilation .......................................... 1183
VII. Bronchial Blood Flow ................................................. 1185
A. Anatomy and physiology of bronchial circulation ................... 1185
B. Effects of pulmonary microembolizatibn on bronchial blood flow ..... 1188
VIII. Conclusions .......................................................... 1191
1114 0031-9333/83 $1.50 Copyright 0 1983 the American Physiological Society

July 1983 PULMONARY MICROEMBOLISM 1115
I. INTRODUCTION
Because the pulmonary circulation receives the entire cardiac output,

it has a major role in filtering emboli that may be present in the systemic
venous blood. With this filtering function the pulmonary circulation protects
the essential coronary, renal, and cerebral circulations during an embolic
episode. However, pulmonary embolism has direct and unique effects on the
lungs. Some effects of pulmonary embolism are homeostatic, whereas others
disrupt lung function. For example, the bronchoconstriction occurring after
embolization redistributes ventilation away from the embolized regions, thus
improving the match betweeen ventilation and perfusion. On the other hand,
pulmonary edema, which also follows embolization, can worsen the hypox-
emia caused by the embolism. The purpose of this review is to examine the
diverse alterations in pulmonary function associated with microembolization
and to review critically the mechanisms proposed to explain these functional
changes.
This review deals with pulmonary microembolism, defined as obstruction
of pulmonary arteries < 200 pm in diameter. Macroembolism, which refers
to occlusion of larger pulmonary arteries, is considered only when the re-
sponses’ to small-vessel and large-vessel obstruction differ.
A. Recent Reviews
The proceedings of a symposium devoted to the pathogenesis of pul-

monary microembolism and the resulting pulmonary and hemodynamic re-
sponses were published in 1973 (344). Moser (343) has reviewed the literature
concerning the clinical manifestations of this problem, and Saldeen (437,
438) has summarized the extensive studies conducted in his laboratory on
the pathophysiology of microembolism, particularly in regard to develop-
ment of pulmonary edema. Certain aspects of the pulmonary response to
microembolism have been discussed in reviews not dealing primarily with
the problem of pulmonary vascular occlusion (297, 384, 470).
B. Pulmonary Microembolism and Throwzbogenesis
A clot in the lumen of a pulmonary artery is usually caused by an

embolism (197, 419). Two factors suggest the embolic nature of such clots:
1) their occurrence in previously normal pulmonary arteries (437) and 2)
their common association with identifiable thrombi in systemic veins or in
the right heart (419, 452). The reticuloendothelial system can modulate the
degree of pulmonary embolism (427). Embolization of pulmonary microves-
sels results when the ability of the reticuloendothelial system to clear cir-
culating microaggregates of fibrin and platelets is impaired (238, 430).
Once lodged in pulmonary vessels, the microemboli may serve as sites
1116 ASRAR B. MALIK Vduww 63
of intravascular coagulation by directly activating the intrinsic coagulation

system (166,437). Secondary pulmonary thrombosis may also occur if there
is so much emboli-induced endothelial damage that the extrinsic coagulation
pathway is also activated by exposure of subendothelial membrane to the
blood components (237, 381, 457). Other causes of secondary thrombosis in
the lungs after pulmonary embolism are states of blood hypercoagulability
(192) and stagnant pulmonary blood flow caused by vascular occlusion
(77, 237).
C Methods of Producing Pulmonaw Microembolism
Pulmonary embolism has been produced injecting substances of various

sizes, shapes, weights, and compositions [e.g., pumice powder (539), lycopo-
dium spores (115), starch granules (60), glass beads (302), fat emboli (433,
435), endotoxin (490), balloons ,(376), collagen suspension (510), and even
gunshot (357)]. Although all these methods obstruct lung vessels, little con-
sideration has been given to the possibility that they produce different al-
terations in pulmonary function. For example, substances such as glass beads
cause intravascular coagulation by activating the Hageman factor (factor
XII) (236, 237), whereas a balloon in a pulmonary artery causing the same
degree of physical obstruction may not produce clotting. The possibility that
different methods of embolization produce the same alteration in pulmonary
function by different mechanisms has also been largely neglected. For ex-
ample, the pulmonary edema after embolization with a balloon embolus may
be due to a hemodynamic mechanism, whereas the edema associated with
infusion of thrombin (EC 3.4.21.5) may be due to vascular injury resulting
from the humoral mediators released because of this challenge (437).
Instead of injecting foreign subtances (such as glass beads) to produce
emboli, some workers have produced pulmonary microembolism by directly
stimulating intravascular coagulation with thrombin (437) or by causing the
release of clots previously formed in peripheral veins (536). These represent
closer paradigms of real embolic disease, because these microemboli consist
of fibrin, platelets, and white blood cells. With thrombin infusion, however,
there is \disseminated intravascular coagulation (300). Intravenous injection
of preformed autologous blood clots is also advantageous, because the em-
bolism is usually localized in the lung. Another advantage of these methods
is that dissolution can be studied (17, 108); this is not possible with foreign
emboli. Embolization with glass beads of uniform size, however, allows better
control over the size of the vessels being obstructed (219,556) than does the
release of preformed venous clots, which usually vary in size and shape.
Nevertheless the studies of Nelson and Smith (357) have shown that clumping
of glass beads may occur in the larger arteries and that emboli advance into
the smaller vessels. Another variable influencing the distribution of mi-
croemboli in the lung is specific gravity: emboli heavier than the formed
elements (e.g., glass beads) gravitate to the dependent lung regions, whereas
lighter emboli (e.g., air emboli) are preferentially distributed to the upper
lung regions (67). Finally, certain emboli may not remain static. For example,
air bubbles probably do not remain at one point within the vessels but elon-
gate within the vasculature and deform as they are pushed further into
smaller vessels (67). Therefore the pulmonary response to air embolization
may change over time as the emboli move from large to small pulmonary
arteries.
Thus when choosing a model of pulmonary microembolism one must
consider whether the embolization is I) only obstructive, 2) associated with
secondary thrombosis, 3) located in small or large vessels, 4) reversible or
chronic, and 5) confined only to the pulmonary vascular bed.
II. PULMONARY HEMODYNAMIC RESPONSE TO MICROEMBOLIZATION
Microembolization clearly produces pulmonary hypertension without

causing changes in left atria1 pressure (Pla) and pulmonary blood flow (265,
301, 376, 390). This observation indicates that the increased pulmonary ar-
terial pressure (Ppa) primarily results from a rise in pulmonary vascular
resistance (PVR). Mechanical obstruction, vasoconstriction, or a combination
of both effects could cause this increase in PVR (530). The following sections
deal with the relative contributions of these factors to the increased PVR
associated with microembolization.
A. Mechanisms of Increase in Pulwwnarvy Vascular Resistance
I. Eflects of mechanical obstruction
Mechanical obstruction of lung vessels after microembolization un-

doubtedly causes a rise in PVR, but the resistance begins to increase ap-
preciably only after -50% of the pulmonary vascular bed has been em-
bolized.
In 1923 Haggart and Walker (172) reduced the cross-sectional area of
the pulmonary artery of cats with a screw clamp and found that the Ppa
increased only after the area had been reduced by more than 50%. Gibbon
et al. (154, 155) restudied the problem in the same species by surgically
reducing the cross-sectional area of the pulmonary vascular bed. They found
that pressure did not begin to increase until more than one lung had been
removed and that pressure increased thereafter in direct proportion to the
amount of lung tissue removed. When only 29% of the lung remained, the
pulmonary hypertension was so great that fatal pulmonary edema ensued.
These authors did not measure PVR in their studies; however, because pul-
monary blood flow and Pla do not change significantly until over 65% of the
1118 ASRAR B. MALIK vdume 63
pulmonary vascular bed is obstructed (103), the PVR in the experiments of

Gibbon and co-workers must have increased (as did the Ppa) in proportion
to the degree of mechanical obstruction.
There are two reasons why it is necessary to obstruct more than 50%
of the pulmonary vascular bed to produce any increase in the Ppa. First,
the arteries and veins of the lung are compliant and canaccommodate two-
to threefold increases in blood volume with only a 1-2 mmHg increase in
pressure (136, 258, 259). Therefore Ppa cannot be expected to increase sig-
nificantly until the pulmonary blood volume has risen 200-300%; this increase
would not occur until more than one lung has been removed. After this point,
small increments in volume produce relatively large increases in Ppa. Sec-
ond, the recruitment of additional pulmonary vessels minimizes the pressure
changes in lung vasculature after vascular obstruction (394). In most studies
this factor was probably less important than the role played by vascular
compliance: because the animals were supine in these experiments, the lungs
were largely in the zone of total vascular recruitment, zone III (537). In zone
III, Ppa is greater than the pulmonary venous pressure (Ppv), which is
greater than the alveolar pressure (PA). However, where there is a discern-
ible zone I (PA > Ppa > Ppv) and a zone II (Ppa > PA > Ppv) with a potential
for greater, recruitment, these regions would minimize the rise in Ppa as-
sociated with vascular obstruction.
z. Active pul-q vasocmtriction
a) EvW supporting vasocmttictim The increased Ppa seen after

microembolization is caused by active pulmonary vasoconstriction as well
as by the passive mechanical effect of obstruction described in section IIAI.
Lee et al. (263) found that selective embolization of a portion of one dog lung
with glass beads 100 pm in diameter caused significant increases in Ppa and
PVR. These changes were not caused by hypoxic pulmonary vasoconstriction
or mechanical obstruction, because the blood gases were normal and no reflux
of beads occurred into the nonembolized lung. A similar increase in PVR has
also been observed in patients with embolic occlusion of ~25% of the pul-
monary vascular bed as determined by angiography (3).
These results are in accord with the earlier finding of Dalen et al. (103)
and Dexter et al. (115) that pulmonary arterial hypertension can be produced
by embolization of ~50% of the pulmonary vascular bed only if the emboli
are ~170 pm in diameter. The Ppa increased after embolization with particles
28-30 pm in diameter; of the 600-280,000 X lo6 vessels of this size present
in the pulmonary circulation, only 22 X lo6 vessels were assumed to be
blocked (Table 1; 15). On the other hand, as seen in Table 1, to produce the
same elevation in Ppa with particles >170 pm in diameter, it was necessary
to inject enough particles to block most of the vessels of this diameter. The
pulmonary hypertension seen after microembolization with the smaller par-
TABLE 1. Numbers and sizes of emboli needed to raise JX&WTUZ~

arterial pressure 5-10 mmHg in dogs
Diameter of Number of Emboli
Artery Type of Emboli Emboli, m m Number of Vessels Injected, mean f 1 SD
Lobar Blood clots 5.0 7 7tl

1st order Glass beads 4.0 18 28t7
2nd order Polystyrene spheres 2.3 40 58 t 20
or blood clots
3rd order Polystyrene spheres 1.0 1,020 1,635 t 289
Lobular Polystyrene spheres 0.3 16,000 28,125 t 10,270
Atria1 Polystyrene spheres 0.17 89,140 t 4,260
Arterioles Lycopodium spores 28-30 pm 600-280,000 x lo6 22 x lo6
From Dalen et al. (103).
titles is obviously due to some mechanism other than simple mechanical

obstruction of the pulmonary vascular bed.
Hyland et al. (202, 203) showed that constriction of pulmonary vessels
by the microemboli (28 pm in diameter) was rapidly reversed by increasing
blood flow through the lung. This decreased resistance could not be dem-
onstrated when embolization was induced by particles 300 pm in diameter
(202,203), however, indicating that the larger emboli did not constrict vessels.
In another study the increased PVR observed in dogs after microembolization
with glass beads 100 pm in diameter was greater than that predicted from
the degree of vascular obstruction (302). The finding that a 50-60s obstruc-
tion of the pulmonary vascular bed caused a disproportionately large in-
crease in PVR [i.e., an increase of 300~500% (302)] indicates microemboli-
zation-induced constriction of pulmonary vessels. Thus active pulmonary
vasoconstriction occurs after microembolization but only when the small
pulmonary arteries (those 470 pm in diameter) are obstructed.
The homeostatic value of pulmonary vasoconstriction has been ques-
tioned because the response appears to constitute a positive feedback. Any
additional vasoconstriction after pulmonary vascular obstruction would fur-
ther increase the right ventricular afterload, and failure may occur if the
increase in PVR is marked (137). Whitteridge (539) suggested that pulmonary
vasoconstriction would be beneficial if constriction was confined to precap-
illary vessels because it would prevent the high Ppa from being reflected to
the filtering microvessels. Experimentation has not yet established whether
reversal of the active pulmonary vasoconstriction seen with microemboli-
zation can actually exacerbate the embolism-induced pulmonary edema.
b) Site of pulmonary vasoconstriction. The pulsatile nature of pulmonary
capillary blood flow, as measured by the nitrous’oxide method, has been used
to determine the site of constriction after embolization (22, 246). The flow
1120 ASRAR B. MALIK Vohmw 6.9
wave generated by contraction of the right ventricle is propelled through the

low-resistance pulmonary arterial system and normally arrives at the cap-
illaries with only minor alterations in shape (246). Embolization of the left
lung lobe, however, resulted in a decreased pulsatility of pulmonary capillary
flow associated with an increased PVR (246). Active vasoconstriction occur-
ring at precapillary sites explained the decreased pulse transmission. The
flow response was only transient [lasting 30 min (246)], which suggests the
effect was related to’ the release of a humoral substance(s), and the response
waned as circulating levels of this substance(s) decreased or as tachyphylaxis
occurred. The reversibility of the response indicated the effect was not simply
due to mechanical obstruction. The value of the nitrous oxide technique for
localizing the site of vascular resistance, however, is questionable-the ap-
proach is indirect and assumes an unaltered pulmonary vascular compliance
(340). Nevertheless these findings suggest pulmonary arteries are the pri-
mary sites of constriction associated with microembolization.
Researchers have not yet determined the size of the constricting pul-
monary arteries after microembolization. The vessels most likely to constrict
are the patent muscular vessels that are near the embolized lung units and
that have diameters of 100-500 pm (410). The hypothesis that microembolism
affects the ,nearby lung segments is supported by the observation that em-
bolization of a portion of the lung causes vasoconstriction in an indepen-
dently perfused lung segment (554). However, Daily et al. (100) have.chal-
lenged this conclusion. They showed that embolization of an isolated and
perfused left lower lobe with glass beads 42 pm in diameter and small
thrombi did not increase resistance in the nonembolized lung. The differences
between these results could be explained by the different experimental pro-
tocols. In one case the isolated lobe was embolized, whereas in the other a
much larger fraction of the lung was embolized (554). The release of the
vasoconstrictor factor(s) after embolization of one lobe is likely to be less
than that associated with embolization of a larger portion of the lung. The
degree of embolization could explain why Daily and co-workers did not ob-
serve vasoconstriction in the nonembolized lung. However, the matter of
constriction of pulmonary vessels close to the embolized regions needs to be
reexamined.
B. Factors Mediating Pulwwnaq Vasoconstriction
1. Neural mechanisms
Sympathetic nerve stimulation causes constriction of pulmonary vessels

(104, 235, 478). There is a great deal of interspecies variation related to the
intensity of the pulmonary vasoconstrictor response seen during sympathetic
nerve stimulation; for example, the constrictor response during sympathetic
nerve stimulation is weaker in dogs than in cats or sheep (104,174,175,206).
This lesser response appears to be related to the paucity of sympathetic

motor innervation of pulmonary blood vessels and vascular smooth muscle
(129, X34, 410). In all species, however, the pulmonary arteries are the pri-
mary sites of the sympathetically mediated constriction (206). The veins
constrict less than the arteries (206), reflecting the sparse innervation and
the relatively uneven distribution of smooth muscle in pulmonary veins (410).
The role of sympathetic efferents in the pulmonary vasoconstrictor re-
sponse associated with microembolization is poorly understood. Several stud-
ies have indicated that sympathetic mechanisms are not involved in the
pulmonary vasoconstriction seen after microembolization (105,309,380,546).
In an isolated and perfused dog lung preparation, pharmacological dener-
vation with the ganglion-blocking agent hexamethonium did not affect the
pulmonary hypertension resulting from embdlization with glass beads 60
pm in diameter (546). Surgical removal of the sympathetic nerves could not
prevent the pulmonary vasoconstriction due to microembolization with ly-
copodium spores 28-30 pm in diameter (150). The pulmonary hypertension
associated with the injection of autologous clots of different sizes was not
altered after total lung denervation (309, 380). Bilateral cervical vagotomy
did not influence the pulmonary hemodynamic response (105), indicating that
vagal mechanisms are also not involved in the vasoconstriction. Finally,
isolated and perfused lungs (a completely denervated preparation) embolized
with glass beads demonstrated a steadily increasing PVR (14, 33, 120, 360).
It can be deduced from these studies that there is little, if any, involvement
of sympathetics or of the vagus nerve in the pulmonary vasoconstrictor
response associated with microembolization.
Although a few studies indicate that sympathetic mechanisms are in-
volved in the vasoconstriction associated with emboli (360,401), it is unclear
why their role was demonstrated in these studies. The increase in PVR after
embolization was attenuated by thoracic sympathectomy (360,399), and the
pulmonary vasoconstriction induced by embolization in an isolated heart-
head-lung preparation was eliminated when the cephalic circulation was
removed (401). With an intact cephalic circulation, the response was blocked
either by bilateral removal of the stellate ganglion and thoracic sympathetic
chains to T4 or T5 or by prior treatment with hexamethonium (401). In an-
other study, embolization of one lung lobe with glass beads caused an im-
mediate increase in perfusion pressure in another isolated and perfused lobe,
an increase that could be prevented by sympathectomy and vagotomy (360).
From these numerous studies it is apparent that the role of neural
mechanisms in the pulmonary vasoconstriction after microembolization dif-
fers from preparation to preparation and among laboratories. A part of the
problem in delineating neural mechanisms is related to the use of lung prep-
arations that are isolated and perfused. The elaborate surgery necessary for
isolated preparations interferes with the sensory and motor innervations of
the lungs (104) and may produce conflicting results. Another experimental
problem is that lungs are not always embolized to the same degree. In some
1122 ASRAR B. MALIK vdurne 63
cases the pulmonary artery stretch receptors, which may activate the sym-
pathetic efferent pathways in the lung (84, 85,262), may not have been fully
stimulated. Stretch receptors are believed to be stimulated by acute disten-
sion of the pulmonary artery, such as that produced by a nonocclusive balloon
(84, 85, 262). The resultant reflex evokes pulmonary vasoconstriction and
hypertension (230). The response was inhibited by surgical dissection of the
pulmonary artery and procaine infiltration into the area of the bifurcation,
suggesting that the reflex was associated with receptors situated at this site
(230). Sympathectomy produced by 6-hydroxydopamine also abolished the
balloon-induced increase in PVR (230), indicating that sympathetic efferents
are activated. Phentolamine and propranolol did not abolish this reflex (230),
suggesting that the responsible efferents are not the classic CY-and P-adren-
ergic receptors.
2. Humoral mechanisms
In contrast to the ambiguities surrounding the involvement of sympa-

thetic mechanisms in mediating the increased PVR seen after microembo-
lization, there are many studies indicating that humoral factors are re-
sponsible fdr vasoconstriction. The same number of glass-bead microemboli
caused greater increases in Ppa and PVR in nonheparinized than in hepa-
rinized animals, whereas the levels of hypoxemia and acidosis were similar
in both groups (301). Because the experimental groups were identical except
for the presence of heparin, the greater increase in PVR seen in the non-
heparinized dogs is somehow related to the release of humoral factors after
intravascular coagulation. Other studies have shown that to elevate PVR to
similar levels in normal and thrombocytopenic animals, twice as many glass
beads must be injected into the thrombocytopenic animals (36). Such studies
support the notion that humoral factors are released from platelets after
their aggregation and activation.
The following section discusses the specific mediators that may be in-
volved in increasing PVR after embolization.
a) Specific mediators. One way to identify the humoral factors that
mediate pulmonary vasoconstriction after microembolization is to examine
the effects of pharmacological agents that inhibit the synthesis or release
of pulmonary vasoactive mediators. Inhibition of prostaglandin synthesis
by cyclooxygenase inhibitors (indomethacin, meclofenamate, or polyphlor-
etinphosphate) and of histamine release (with chlorpheniramine and meth-
amide) attenuated the increased PVR produced by glass-bead injection into
dog lungs (500). The obvious conclusion is that prostaglandins and histamine
are responsible for pulmonary vasoconstriction; these data do not provide
definitive proof, however, because these antagonists may have independent
pulmonary vasodilator effects (499).
The finding that both histamine and the products of cyclooxygenase
pathway [thromboxane A2 (TXA2) and prostaglandins] are present in in-
creased concentrations in the venous blood draining embolized lungs (432)

nevertheless provides additional evidence involving these factors in the pul-
monary vasoconstrictor response. Pulmonary vasoconstrictor agents such as
TXAz are released after microembolization by aggregated platelets and leu-
kocytes in the pulmonary circulation (207, 561). Histamine is released from
the mast cells situated in the extravascular space (13, 269) and, to a lesser
extent, from the basophils sequestered in the lungs after embolization (269,
272). In spite of these rather convincing data, a causal relationship between
the release of these vasoactive factors and the pulmonary vasoconstriction
associated with microemboli has not been firmly established. In fact, the
observations that histamine (Fig. 1) and TXA2 appear to constrict primarily
the pulmonary veins (47, 175, 374) would argue against these substances as
primary mediators of the pulmonary arterial constriction associated with
microembolization.
Because serotonin (on a molar basis) is the most potent constrictor of
pulmonary precapillary vessels (Fig. 1; 207), Comroe and colleagues (88)
1
7
HISTAMINE ) ( (NS) (0.003) t 1
NOREPINEPHRINE
PROSTAGLANOIN Fz, k+k
SEROTONIN (0.001) U-1 t-i
HYPOXIA
STIMULATION
CONTROL
t-:::14:. l-i
.
l-i
1
UPSTREAM DOWNSTREAM
I
15 10 5 0 5 10 15
PRESSURE DROP (TORR)
FIG. 1. Effects of various pulmonary vasoconstrictor stimuli on upstream (arterial) and
downstream (venous) pressure drops measured using the venous outflow occlusion method.
Numbers in parentheses are P values comparing upstream and downstream pressure drops with
control. Stimulation refers to stimulation of stellate ganglion. All stimuli except histamine
caused greater increase in arterial resistance than in venous resistance. NS, not significant.
[From Hakim et al. (175).]
1124 ASRAR B. MALIK Vohme 63
postulated this compound as the mediator of the smooth muscle contraction

associated with emboli: a constant infusion of serotonin caused marked pul-
monary hypertension that persisted as long as the infusion lasted. Knisley
et al. (251) postulated a rather unique explanation for the pulmonary hy-
pertensive effect associated with serotonin. They observed that serotonin
infusions produced a fine white precipitate [possibly serotonin-mediated
platelet aggregation (378)] within the pulmonary arteries; this precipitate
disappeared soon after its formation. Because of its rapid disappearance, the
precipitate cannot explain the sustained hypertension, which indicates that
serotonin probably has a direct effect on pulmonary vascular smooth muscle.
The finding that precapillary pulmonary vessels are the primary sites of
constriction after both serotonin infusion (Fig. 1; 175) and microembolization
(246) supports the hypothesis proposed by Comroe that serotonin is the pri-
mary mediator of the microemboli-vasoconstrictor response.
The release of serotonin after embolization has been studied in a dog
lung preparation in which a left lower lobe was isolated and perfused at a
constant flow rate (554). Embolization of the remaining lung with autologous
clots 150-250 pm in diameter caused an increased Ppa, followed by increased
arterial and venous pressures in the perfused lobe at 45 s after the peak
pressor response occurred in the embolized lung. These changes were ac-
companied by increased serotonin levels in pulmonary venous blood draining
the nonembolized lung (544). Heparin prevented the increased vascularpres-
sures and the release of serotonin (554), which indicates serotonin is released
as a consequence of thrombosis. Prevention of serotonin release with heparin
may explain why the increased PVR seen after glass-bead microembolization
was greater in nonheparinized than in heparinized dogs, although the same
degree of vascular obstruction was present in both conditions (301).
Whether the increased serotonin concentration measured in the pul-
monary venous effluent is a result of increased liberation or decreased break-
down by the pulmonary endothelium (138,229) has not been examined. Pos-
sibly serotonin, which is released after platelet aggregation (90, 346), is not
degraded to the same extent as in normal lung during its passage through
the pulmonary circuit (229). Serotonin may also be released in such large
quantities that the enzyme system responsible for its inactivation is satu-
rated (229). Serotonin also appears to reach the nonembolized lung via the
bronchial circulation (112) and to constrict the vessels in the unobstructed
lung as well as the vessels closer to the embolized blood vessels.
Therefore the most likely humoral mediators of the pulmonary vaso-
constrictor response after microembolization are TXA2,’ histamine, and se-
rotonin. A definitive conclusion as to which is the most important cannot
be made at this time.
b) P&eZet aggregation, Because vasoactive substances such as serotonin
and TXA2 are associated with the pulmonary vasoconstriction observed after
microembolization (41, 88, 476, 507), it is not surprising that the role of
platelet aggregation has been extensively studied. Platelets are the major
source of the serotonin released after microembolization (461,492,534), and

platelet aggregation is associated with the release of other pulmonary va-
soconstrictor substances such as the prostaglandins prostaglandin Fz,
(PGF,,), TXA2 (511-513), and histamine (432, 448, 500, 504).
The involvement of platelet aggregation in the pulmonary vasoconstric-
tor response has been examined by injecting collagen fibrils into one lung
to produce unilateral platelet aggregation, which resulted in a diversion of
flow to the normal lung (40). Flow redistribution was prevented after pro-
ducing thrombocytopenia with antiplatelet serum (40), indicating a direct
involvement of platelets in the response. Also, the increased PVR seen after
microembolization was reduced by thrombocytopenia (36, 41, 335) and by
both indomethacin (476, 500) and aspirin (304, 403), which inhibit platelet
aggregation by preventing the generation of TXAz (144, 207). In another
related study, twice as many glass-bead microemboli had to be injected into
the pulmonary circulation of thrombocytopenic sheep to produce the same
increase in PVR caused by the beads in normal sheep (36). These findings
indicate the importance of platelets in producing the pulmonary vasocon-
strictor response seen with microembolization.
c) Active pulmonary vasodilation. Microembolization sometimes causes
pulmonary vasodilation rather than constriction (244). Vasodilation has been
observed in a lobe perfused at a constant flow rate when the remaining lung
has been embolized (244). Vascular resistance may decrease over time in an
embolized lung segment because small emboli may gradually be pushed into
smaller vessels, resulting in a decreased obstruction of the larger vessels in
the pulmonary vascular bed. The resultant decrease in total PVR may er-
roneously be thought to represent pulmonary vasodilation. However, in the
study by Kealey and Brody (244), vasodilation occurred in the segment of
the lung that was not embolized, and the vasodilation was prevented by
cervical vagotomy. Atropine had no effect, indicating that the response to
microemboli was due to vagal afferents. The response was also inhibited by
hexamethonium, sympathetic denervation, and propranolol (244), indicating
it was associated with a vasodilator component of the sympathetic efferents,
possibly P-adrenergic receptors. Like the pulmonary vasoconstrictor re-
sponse, vasodilation depends on the size of the emboli: vasodilation was not
observed with beads averaging 130 pm in diameter but was seen with beads
64 pm in diameter (244).
The receptors involved in this reflex have not been identified, although
baroreceptors with vagal nerve afferents have been found in the bifurcation
of the main pulmonary artery and in the proximal portions of right and left
pulmonary arteries (81,84,364). But stimulation of pulmonary baroreceptors
by distension of a pulmonary artery with a nonocclusive balloon produces
pulmonary vasoconstriction, not vasodilation (204, 230). It is therefore nec-
essary to invoke another set of receptors in the small precapillary vessels
that are located upstream from the microemboli and that evoke the reflex
vasodilation.
1126 ASRAR B. MALIK t%hne 6.9
d) Efects on pulmonary vascular compliance and blood volume. Few ob-

servations have been made concerning the effects of pulmonary embolization
on overall or regional pulmonary vascular compliance. Alpert et al. (4) as-
sessed “pulmonary vascular compliance” by measuring the ratio of pulmo-
nary blood volume to mean Ppa. Embolization of a large pulmonary artery
with a balloon catheter caused a greater decrease in the ratio than embo-
lization of smaller pulmonary arteries with glass beads 100 pm in diameter.
The ratio returned to base line 30 min after microemboli injection, whereas
the decrease was sustained after balloon embolization. The differences in the
compliance observed after microembolization might have been due to ob-
struction of small arteries downstream from the large capacitance vessels;
thus compliance was not as severely restricted as after embolization of the
large pulmonary arteries, which primarily obstruct the compliant portion
of the pulmonary vascular bed (4), that is, the larger pulmonary arteries.
The transient nature of the decrease in pulmonary vascular compliance
after microembolization (4) suggests that the compliance change, like pul-
monary vasoconstriction, is humorally mediated. The humoral factors re-
sponsible for the decreased compliance may be the same as those mediating
the increased pulmonary vascular resistance associated with microembolism
(i.e., TXA2, serotonin, and histamine).
e) Regional pulmona77/ blood&w. Pulmonary microembolization alters
the regional distribution of pulmonary blood flow, but the redistribution
pattern depends on the region of the lung embolized. Glass beads tend to
obstruct primarily the more dependent pulmonary vessels because the flow
to this region is greater than that to the upper lung (301, 303). Also the
beads tend to gravitate toward the dependent lung regions because they are
heavier than the formed elements (206). The blood flow is redistributed away
from the dependent lung regions owing to preferential embolization of the
dependent lung and localized vasoconstriction occurring in regions of the
lung receiving the emboli (39, 40). Air emboli, however, preferentially em-
bolize the upper lung regions, increasing the blood flow to the dependent
portions of the lung (67). Microemboli with specific gravities similar to those
of formed elements (e.g., fat microemboli and microthrombi) are distributed
relative to the regional blood flow without a redistribution of blood flow (24,
300). Therefore the patterns of blood flow observed with microemboli seem
solely dependent on the specific gravity of the embolic material relative to
that of the blood-formed elements.
The major consequence of flow redistribution after emboli is the effect
on matching (or mismatching) of alveolar ventilation @A) and perfusion
(a). Because decreased ratios of ventilation to perfusion (i.e., decreased VA/
& values; see sect. VI) are the major cause of hypoxemia after microembol-
ization (see sect. IV), it follows that flow-redistribution patterns resulting
from different forms of microemboli produce regional VA/Q values that cause
varying degrees of hypoxemia.
Decreased pulmonary perfusion persists even after dissolution of the

microthrombi (101, 108, 417). This has been observed in coronary (76, 545),
cerebral (64), and renal (143) vascular beds after periods of vascular occlu-
sion. Swelling of capillary endothelial cells induced by short periods of oc-
clusion (261, 286, 545) was hypothesized to cause the elevated resistance
during reperfusion. A period of pulmonary vascular occlusion may similarly
injure the microvascular endothelial cells and contribute to abnormal re-
gional perfusion, but this has not been determined in the pulmonary cir-
culation.
III. PULMONARY EDEMA AFTER MICROEMBOLIZATION
In the lung an increased extravascular water content is commonly ob-

served after embolization of pulmonary microvessels (302, 376, 437). The
following section reviews the basis of the edema associated with microem-
bolization, discusses the site of fluid exchange and accumulation, and pre-
sents the mechanisms believed to be responsible for edema formation.
A. Efebts of Pulmonary Microembolism on Lung Fluid Balance
Two factors have been proposed to explain the development of pulmo-

nary edema after microembolization (376,437): I) an increased microvascular
hydrostatic pressure and Z) an increased microvascular permeability to en-
dogenous plasma proteins. The pressure is elevated in some microvessels if
the increased Ppa associated with pulmonary vascular obstruction is trans-
mitted to unobstructed microvessels (154,155). The increase in microvascular
pressure (Pmv), if it occurs, has not been measured by direct techniques in
either unobstructed or obstructed regions of the lung (286). Pulmonary
edema may also result because the pulmonary microvessel permeability to
proteins is increased either by mechanical injury of the microvessel wall or
by the release of some humoral or cellular substance that acts directly on
the microvascular permeability (50, 51, 471).
1. Pulmonary fluid and protein exchange
a) Shep studies. Pulmonary lymph (i.e., a measure of the net plasma

filtrate) can be collected from the efferent duct of the caudal mediastinal
node draining sheep lungs (126, 470). Because the changes in pulmonary
lymph flow (&lYm) and the protein concentration of the lymph can subse-
quently be measured, this experimental model has been useful in describing
the events that cause pulmonary edema. Microembolization of the lung in-
variably increases the transvascular filtration of fluid in lungs even though
1128 ASRAR B. MALIK vohne 6s
a significant portion of the pulmonary vascular bed has been obstructed and
cannot contribute greatly to Qlyrn (303, 311, 376). An increased vascular sur-
face area available for filtration cannot explain the increased capillary fil-
tration, because microembolism obviously decreases filtering area (303).
The increased pulmonary Pmv also fails to explain the increased trans-
vascular fluid filtration, because Qlym increased after embolization, whereas
the ratio of the lymph-to-plasma protein concentration (L/P) remained un-
changed (376) or even increased (303). Figure 2 shows the effects of glass-
bead embolization on Qlyrn and on albumin and globulin L/P values in a
sheep. A similar increase in Qlyrn induced by an increase in Pmv in a normal
lung was invariably associated with a decrease in L/P (Fig. 3, A and B; 126,
331), a finding quite different from that noted after microembolization (Fig.
2). Therefore the relatively large increase in transvascular protein clearance
(&,, X L/P) after microembolization probably represents an increased per-
meability of pulmonary microvessels to plasma proteins.
That pulmonary microembolization increases lung vascular permeabil-
ity was clearly demonstrated in other studies by increasing Pmv after mi-
croembolization (294, 375). When the capillary wall is more permeable to
proteins, a given increase in Pmv results in greater increases in Qlym and in
transvascular protein clearance than those seen in normal lung capillaries
(488). This change occurs after pulmonary embolization induced by either
air bubbles (375) or thrombin (294). Figure 4 shows that the increase in. Pmv
induced by inflation of a left atria1 balloon after thrombin resulted in a large
SHEEP ‘3
FIG. 2. Time course of ef-

fects of progressive pulmonary
microembolization on pulmonary
lymph flow (&,) and ratios of
lymph-to-plasma concentrations
(L/P) of albumin and globulin in
sheep. Injections of glass-bead
microemboli are indicated by El,
.8Op EZ, and ES. Increase in pulmo-
nary vascular resistance (PVR)
ALBUMIN
.60y after El is small, reflecting injec-
tion of few emboli, and PVR in-
creases progressively as bed is
further embolized (E2 and ES).
Increase in transvascular protein
clearance ( Qlym X L/P) is rela-
tively large after El despite min-
imal increase in PVR. [From Ma-
lik and van der Zee (303).]
HOURS
ISHEEP C-3
1 ----r----l _____ J-----=----1 ______
10 ,-- ---a----
0t
-60 0
4
i
I
60
MINUTES
120 I80
I”L--
0 IO
Pulmonary
20 30
mi~rovascular
40
Pla pressure, cmHzO
FIG. 3. A: effects of raising left atria1 pressure (Pla) in sheep by inflating left atria1 balloon.
Qlym, pulmonary lymph flow; L/P, ratio of lymph-to-plasma concentrations of protein; CL, trans-
vascular protein clearance ( Qlym X L/P); Ppa, mean pulmonary arterial pressure; Pla, mean Pla.
Increase in Pla increased Qlyrn and decreased L/P because of greater movement of water than
of proteins across microvessels. B: relationship between calculated pulmonary microvascular
pressure (Pmv) and L/P; Pmv = Pla + 0.4 (Ppa - Pla) (where Ppa is mean left pulmonary
arterial pressure); 0.4 = fraction of total resistance in downstream pulmonary vascular segment.
[From Minnear et al. (331).]
increase in Qlym without a change in L/P, providing further proof that ob-
struction of pulmonary microvessels increases pulmonary vascular perme-
ability.
Because these observations in sheep involved lymph collected from the
efferent lymph duct of the caudal mediastinal node (126,470), it is important
to understand the assumptions involved in using this preparation to assess
vascular permeability. A major assumption is that the lymph and interstitial
fluid protein concentrations are similar. Guyton et al. (168) have argued that
this assumption may not be tenable because a positive hydrostatic pressure
in the terminal lymphatics could result in the movement of water out of the
lymphatics into the interstitial tissue, thereby increasing the lymph protein
concentration. Also the protein concentration can be altered as the lymph
passesthrough the caudal mediastinal node (413), because water and solutes
may be exchanged across nodal blood and lymph vessels (11,413). This mech-
1130 ASRAR B. MALIK vohne 6.9
THROMBIN CONTROL
I
I
-60 0 60 120 180 240 300

4 f
THROMBIN PIa
MINUTES
FIG. 4. Effects of thrombin on pulmonary lymph flow (&,,), ratio of lymph-to-plasma
protein concentration (L/P), transvascular protein clearance (CL), mean pulmonary arterial
pressure @pa), mean left atria1 pressure @la), and pulmonary vascular resistance (PVR). In-
crease in PVR after thrombin-induced microembolization increased QIYm and L/P. Increase in
Pla induced by balloon further increased &1, but without significant change in L/P. This
contrasts with effects of left atria1 hypertension in normal lungs (Fig. 3, A and B), indicating
that thrombin increases pulmonary microvascular permeability to proteins.
anism could be particularly crucial when lymph flow rates are normal or
low. However, it is unlikely that the lymph concentration changes during
high flows. If lymph protein concentration is altered by either of these mech-
anisms, any conclusions regarding endothelial permeability changes after

microembolization may be in error. Despite these possibilities, there is no
experimental proof to indicate that the pulmonary lymph protein concen-
tration is different from interstitial fluid protein concentrations (11). The
lymph and interstitial protein concentrations were similar when edema was
produced either by increased Pla or by increased permeability associated
with Pseudomonas bacteremia (522-524). There was, however, a great deal
of scatter (522), possibly because the interstitial samples were from discrete
regions, whereas lung lymph represents an integrated sample. The most
reasonable conclusion from these studies is that afferent lung lymph and
interstitial free fluids are identical. Autoradiographic assessment of albumin
concentration in different-sized lymphatics in mouse lung (359) and in sheep
lung (N. C. Staub, unpublished observations) indicate no major differences
in protein concentrations between small and large lymphatics.
There is another problem related to the interpretation of data obtained
from the procedure described above. The efferent duct of the caudal me-
diastinal node in sheep drains only about two-thirds of the posterior lung
(376, 470). However, as discussed in sect. IC, microemboli may obstruct se-
lective regions that may be different from the lymph drainage sites (67,301,
303). If the site of embolization differs from the lung region that is drained
by the pulmonary lymphatic, the lymph flux data does not reflect events in
the embolized portion of the lung. But in the glass-bead studies, the posterior
region of lung was embolized 301), and this was also the region from
which lymph was collected (376,470), indicating that the lymph data reflect
the permeability increase in the region of the lung receiving the emboli.
A final problem in using the sheep preparation is possible contamination
of pulmonary lymph by extrapulmonary sources, such as the diaphragm and
esophagus (117). An increased systemic venous pressure induced by pul-
monary vascular *obstruction could increase the lymph flow by increasing
the diaphragmatic or esophageal inputs into the lymphatic; however, this
should be associated with a decreased L/P rather than with the unchanged
or increased L/P observed after microembolization (303, 376). Moreover an
increased permeability was evident after microembolization even in para-
lyzed animals (303, 376); the effect of diaphragmatic contractions on lymph
flow was minimized in these animals (117, 422). Also, raising Pmv should
produce a greater pulmonary filtrate component in the lymph and thus
should minimize any contribution from systemic sources (375); therefore the
observation that the increased Qlym after an increase Pmv in embolized lungs
was associated with an unchanged L/P clearly indicates an increased per-
meability (294, 375).
b) Dog studies. An increased lung vascular permeability has also been
demonstrated in dogs after thrombin-induced pulmonary microembolization.
Some of these data are difficult to interpret, however, because the right duct
lymph was used to assess lung vascular permeability (44). In dogs at least
40% of the lymph in the right duct comes from extrapulmonary sources (521).
1132 ASRAR B. MALIK Vohww 63
A more direct indicator of increased lung vascular permeability in this study

was the finding that the protein concentration of tracheal edema fluid after
thrombin embolization approached the plasma values (44). Minnear and col-
leagues (331a) showed by means of a prenodal hilar lung lymph preparation
in the dog (488; A. E. Taylor and J. C. Parker, manuscript in preparation)
that thrombin embolization produced an eightfold increase in protein-rich
lymph flow. This finding supports the sheep data even though in the sheep
studies Qlyrn never increased more than 300-400% after similar increments
in PVR *with thrombin (303, 375). Thrombin decreased the plasma protein
reflection coefficient [a measure of microvascular barrier restriction to flow
of plasma proteins (471)] in dog lungs from a normal value of 0.65-0.70 to
0.49 (331a), indicating an increase in pulmonary microvascular permeability
to proteins.
In another study the extravascular lung water content was increased
in dogs by 60-80s within 1 h after glass-bead embolization that produced
a 35 mmHg increase in Ppa (302). Although the extent of alveolar flooding
was not determined, this probably occurred in most of the animals, because
increases in the extravascular water content of SO% are usually associated
with accumulation of fluid in air spaces (295). The rise in Ppa was clearly
not responsible for the rapid and severe edema because a similar increase
in pressure did not produce edema within the same time period (167). The
most likely explanation for the edema formation, which substantiates the
data obtained from sheep lymph, is an increased endothelial permeability
associated with microembolization.
c) Studies of isolated and perfused lungs. The capillary filtration coef-
ficient (CFC) and fluid filtration rates of isolated and perfused cat lungs were
increased after microembolization induced by collagen fibrils (510). The in-
creases were independent of Ppa alterations-the changes persisted when
the pressure rise was prevented by pretreatment with a pulmonary vaso-
dilator, papaverine (510). Because the increases in CFC and filtration rate
were independent of any pressure rise and occurred even as vascular surface
area decreased, it can be concluded that lung vascular permeability probably
increases after microembolization.
B. Eflects of Increasing Degree of Embolixation
Malik and van der Zee (303) examined the effects of increasing amounts
of pulmonary microembolization in sheep. Pulmonary lymph flow and L/P
increased after only a 30% rise in PVR, as shown by the initial step increases
in Qlym and L/P in each animal (Fig. 5; 303). This suggests that lung vascular
permeability was increased and that it was independent of the increased
Pmv because it was associated with a 2 to 5-mmHg increase in Ppa. This
study also indicates that a minimal degree of pulmonary vascular obstruction
is required to increase vascular permeability, because the increase was ev-
ident with only a 30% rise in PVR.
FIG. 5. Relationship between

steady-state alterations in pulmo-
nary lymph flow (QIYm) after glass-
bead pulmonary microembolization
in 6 sheep and ratios of lymph-to-
plasma concentration (L/P) of glob-
ulin, albumin, and total protein. As
.
Qlym increased after first emboliza-
tion (i.e., initial change in Qlyrn), L/
P also increased, but L/P did not
change after further increases in
.
Qlym as lung was further embolized.
After third embolization, Qlym ac-
tually decreased in some cases. [From
Malik and van der Zee (303).]
1 I I 1 I I J
0 5 IO 15 20 25 30
Q lym 3 ml/ hr
As the vascular bed was further embolized so that PVR was elevated
by 130% from base line, Qlym increased to a higher level, while L/P remained
elevated (303). Figure 5 shows this relationship between Qlym and L/P after
the second embolization. The increase in Qlym was not due to the concomitant
increase in pressure, because an increase in Pmv would have resulted in
ultrafiltration and in a decreased L/P (126, 331). Ohkuda et al. (375) have
also observed that increases in Qlym and transvascular protein clearance after
air embolization were proportional to the degree of obstruction. After mi-
croembolization, however, a point is reached at which increasing the degree
of obstruction does not produce a further rise in Qlyrn or protein clearance.
In studies with glass beads this occurred when emboli obstructed -70% of
the pulmonary vascular bed (303). In some cases Qlym actually decreased
after the final embolization (Fig. 5).
The failure of Qlym to increase with further vascular obstruction is prob-
ably due to a severe reduction in the vascular surface area, which counter-
acted the increased permeability effect. Ohkuda et al. (375) demonstrated
this point by showing that obstruction of diaphragmatic lobes, which are
primarily drained by the efferent duct lymph flow in the sheep, decreased
the rate of Qlym, whereas the same degree of obstruction of upper lobes
Air Infusion
f .-.-.- 1
A f I
t'i
Lting
L mph
i! ow 20
(ml/hr)
0 1 1 I I I I 1 1 1 1 I
0 2 4 6 8 10
HOUrS
FIG. 6A. Effects of pulmonary embolization with air on pulmonary lymph flow. In each
case a similar degree of embolization was induced in the same sheep, whereas duration of air
infusion was different. Increase in lymph flow is related to duration of air infusion, and increase
in each case is reversible. Recovery time was prolonged in proportion to duration of air infusion.
[From Ohkuda et al. (379.1
increased Qlym. Thus the lack of change or even the decreases in Qlyrn and
protein clearance seen after severe microembolization are due to decreased
vascular surface area. All studies must take into account the effect of de-
creased vascular filtration area associated with microembolization.
C. Reversibility of Increases in Permeability
Vaage et al. (510) observed that the increased fluid filtration measured
in isolated and perfused cat lungs after collagen-induced microembolization
lasted only 30 min, indicating the effect was reversible. In addition Ohkuda
and
. colleagues (375) have shown in sheep that the duration of the increased
Qlym and transvascular protein clearance depended on both the duration of
the embolization period and the severity of vascular obstruction. Figure 6A
Air Infusion PPA km Hz01

- 50
-.- 40
0
1 1 1 I 1 1 1 1 1 I 1
0 2 4 6 8 10
Hours
FIG. 6B. Dose response of lung lymph flow ,to pulmonary embolization with air infusion
for 1 h. Both peak lymph flow and recovery period are proportional to obstruction. Dashed line,
60% increase in PVR; dotted and dush,ed line, 100% increase in PVR; solid line, 200% increase
in PVR; Ppa, mean pulmonary arterial pressure. [From Ohkuda et al. (375).]
shows the effects of a similar degree of embolization (i.e., effects of similar

increments in PVR) but of a varying duration of air infusion. Figure 6B
shows the effects of varying the degree of obstruction but at a constant
duration of air infusion. In Figure 6A the period of increased Qlym is different
despite similar vascular obstruction, indicating that the duration of embo-
lization is an important determinant of reversibility. In addition the degree
of vascular obstruction also determines reversibility because a greater ob-
struction (Ppa = 50 cmHzO) produces a longer-lasting increase in Qiyrn than
less-marked obstructions (Fig. 6B).
The rapidity with which lung vascular permeability returned to normal
after microembolizaGon suggests there were no gross morphological changes
in the microvessel wall (92,201); in contrast, the endothelium is denuded and
the vascular injury is irreversible when damage is induced by more toxic
agents such as oleic aeid or alloxan (92, 201).
The ability of the lung to recover from embolic damage is further sub-
1136 ASRAR B. MALIK Vohne 63
stantiated by the finding that pulmonary edema formed at 2 h after em-

bolization was ~50% of that measured at 1 h after the same degree of
embolization (295). The decreased extravascular lung water content was
probably not a result of lowered Pmv because Ppa was the same. Also lym-
phatic removal of extravascular lung water during this period is small, con-
sidering that the maximum increase in the rate of QIYrn is only 20-25 ml/h
(303, 375). The most plausible explanation for the reduction in edema is an
actual time-dependent reduction in capillary wall permeability.
Because cellular and humoral systems have been postulated as the fac-
tors responsible for the membrane changes (302, 437), dissipation or inac-
tivation of these mediators may cause the reversible increase in permeability.
The decreased pulmonary edema measured at 2 h postembolization appeared
to be related to less intravascular coagulation, as compared with the first
hour (295). This finding supports the notion that the decreased permeability
with time is somehow related to local concentrations of blood-borne factors
that alter vascular permeability.
D. Murphological Alterations in Lung Endothelium
The interendothelial junctions in pulmonary microvessels were dilated

after thrombin-induced pulmonary microembolization in dogs (92,240,447).
This change in vascular leakage sites can explain the increased transvascular
protein clearance observed after microembolization in dogs (92) and in sheep
(303, 376). Moosavi et al. (338a), in an ultrastructural study, have also em-
phasized that interendothelial junctions are the primary sites of protein
leakage after air microembolization. Moreover after air embolism the lesions
were confined to small pulmonary arteries (338a), which are also the sites
at which air emboli are lodged (375). Because thrombin-induced microemboli
may lodge in arteries, capillaries, and veins, the alterations in interendoth-
elial junctions may even extend downstream from the arteries. In fact, car-
bon-labeling studies in pulmonary edema induced by either cy-naphthylthi-
ourea (ANTU) or pyrrolizidine indicated that protein leakage occurred only
in pulmonary capillaries and veins and to a lesser extent in small pulmonary
arteries (99). Carbon labeling was not observed, however, in the larger ar-
teries and veins (99). The fluid accumulation within the spaces surrounding
large vessels and airways in the hilum in the’ earlier stages of pulmonary
edema reflects the high compliance of these loose connective tissues rather
than vascular injury occurring at these sites (99, 486).
The interendothelial gaps in capillaries and veins developed’during the
period of edema formation but were not detectable when fluid accumulation
had ceased (99). These temporary changes in junctional dimension are sig-
nificant: Poisueille’s equation predicts that even small increases in junctional
diameters will markedly alter fluid and protein movement, because fluid flow
is directly proportional to the fourth power of the radius of the capillary
wall pathways for solute and solvent fluxes. Therefore the development of
extensive pulmonary edema does not require wholesale destruction of the
microvascular endothelial barrier but can result from the formation of dis-
crete and transient focal lesions.
Although at present there is no explanation for the dilation of endo-
thelial junctions after microembolization, cellular and humoral factors are
undoubtedly involved in the process. Majno et al. (291,293) described similar
junctional widening in skeletal muscle venules after infusion of histamine
or bradykinin. Cotran (93,94) noted a similar condition after thermal injury,
as did Movat and Fernando (345) after endotoxin challenge. These workers
suggested that endothelial open junctions are the sites of protein leakage
and that they result from a reversible contraction of endothelial cells con-
taining actin-myosin cellular microfilaments (291, 293). The venular endo-
thelial cells should easily be distinguished from cells at other vascular sites
because a) their cell bodies bulged into the lumen, b) their nuclei changed
from ovoid to round in appearance, c) folds usually appeared on the abluminal
cell surfaces, and d) cellular microfilaments 40-70 A in diameter were present
(290). Even though the sites of the small vessels were not localized, similar
structural changes also occurred in the pulmonary endothelium after mi-
croembolization (92, 338a), indicating that the endothelial cells in the lung
exhibit similar contractile responses. In this regard it would be important
to examine whether &-adrenergic agonists (such as terbutaline and isopro-
terenol) reverse the microembolization-induced increase in pulmonary en-
dothelial permeability: Svensjii and co-workers (480) have reported that
these’ agonists decrease the histamine- or bradykinin-induced permeability
changes in systemic venules. Because cellular elements appear to be involved,
the effects of other agents such as colchicine and cytochalasin B, which
impair cell contraction by disrupting cellular microtubules (25 A in diameter;
552) and subplasmalemmal microfilaments (5-7 A in diameter; 484), respec-
tively, would also be helpful in elucidating the mechanisms responsible’of
the increased permeability changes.
Another alteration seen in the microvascular wall with microemboli-
zation is an increased number of pinocytotic vesicles in the endothelial cells
(92, 412). Although several investigators have proposed that protein trans-
port occurs primarily via plasmalemmal vesicles (99, 525), the increased
number of vesicles seen during microembolization does not necessarily imply
an increased endothelial permeability. A pulmonary Pmv elevation of 15-20
mmHg doubled the density of endothelial cell vesicles (111) but did not
increase transvascular protein permeability (470). Because vesicle formation
should be an energy-dependent process (70,415,416), studies have also been
made in hindlimbs (416) and in lungs (70) that were perfused at 15OC to
determine the effect of cooling on edema formation and protein transport.
In these experiments the transfer of albumin across capillaries was similar
at 36OC and at 15°C suggesting that an energy-dependent capillary pino-
cytosis is an unimportant component of macromolecular transport across
capillary walls. In addition pulmonary edema formation was not depressed

at lower temperatures (70).
A more likely mechanism by which pinocytotic vesicles contribute to
increased protein transport is by formation of transcellular channels. These
channels (100-1000 A in diameter) are produced by fusion of two or more
vesicles (412,459). In isolated and perfused frog mesenteric capillaries it has
been shown that the pathways are long-lived and that they provide a route
for the increased transendothelial protein transport (75). The major diffi-
culty with using the transcellular hypothesis to explain protein leakage sites
is the extreme rarity of these structures in capillary walls of mammals.
Many investigators have not found transendothelial channels in their prep-
arations (57). In one study Bundgaard (57) did not find vesicular channels
even in the very thin sections of the endothelium in over 700 sections! Against
this background it seems reasonable to conclude that the increased passage
of plasma proteins into the pulmonary interstitium after microembolization
occurs primarily through dilated gap junctions and not through transen-
dothelial channels. Nevertheless any future work should include serial sam-
pling to demonstrate the transendothelial channels that may only appear
as endothelial vesicles in the usual sectioning procedures.
E. Microvessels Versus Arteries as Sites of Fluid and Protein Exchange
A greater surface area is available for filtration in the pulmonary mi-

crovessels (the vessels ~50 pm in diameter) than in the larger vessels; there-
fore it is not surprising that most of the fluid and solute should occur at
this level of microcirculation (470, 473). The situation is altered, however,
when pulmonary arteries are obstructed, as after microembolization. Iliff
(208) raised either Ppa or Ppv in static blood flow to isolated lungs in which
the alveolar vessels had been compressed by increasing alveolar pressure to
values much greater than arterial pressure. Under these conditions, this rise
in pressure increased filtration. This presumably reflected increased filtra-
tion at the level of larger vessels (i.e., extra-alveolar vessels) because the
alveolar vessels were obstructed. In another study, fluid cuffs were observed
around larger blood vessels after complete obstruction of the pulmonary
artery with glass beads (449,538). Albert et al. (1) also demonstrated a steady
weight gain in an isolated and perfused lung after increasing Ppa despite
obstruction of the lobe with glass beads. The edema could only be explained
by an increased transarterial filtration, because the lungs in these studies
were completely obstructed by emboli.
Although these studies demonstrated that fluid filtration can occur
across pulmonary arteries after embolization, this does not mean that pul-
monary arteries are the primary sites for fluid and protein leakage after
microembolization. The studies cited above represent total obstruction of
pulmonary arterial inflow. In most types of microembolization, however, the
microvessels are still perfused through collateral branches originating up-
stream from the obstruction points (248,254). The small pulmonary vessels
can thus participate in fluid exchange in spite of upstream obstructions.
The permeability lesions appear to be confined to the small pulmonary
vessels (92, 201). Studies in sheep demonstrated increased vascular perme-
ability after embolization of vessels with beads 200 pm in diameter, but
beads 500 pm in diameter did not alter vascular permeability (219).
F. Hemodynumic Mechanisms Associated With Increased Permeability
1. Blood velocity
The diversion of the entire cardiac output through unobstructed lung

regions and the resultant decrease in the cross-sectional area of the pul-
monary vascular bed increases the blood velocity after microembolization.
Ohkuda et al. (376) proposed that the increased velocity and the resultant
increases in tangential and shear stresses after microembolization could
injure the pulmonary endothelium. This mechanism had previously been
shown to damage walls of systemic vessels (110, 157). Damage to the aortic
endothelium, which was subjected to high shear rates, was shown to be
associated with “leaky endothelium” (119, 149, 150). Yet the evidence does
not support this hypothesis as the cause of microvascular damage in the
lung. The degree of pulmonary vascular obstruction, as reflected by increased
PVR, was not correlated with the degree of pulmonary edema (59). Moreover
the pulmonary vascular permeability increased with an increase in resistance
as small as 30% above base line (303), where changes in blood velocity were
minimal.
The most complete study concerning velocity effects is that of Landolt
et al. (256). These researchers examined the independent effect of blood ve-
locity on lung fluid and protein exchange in sheep by resecting 65% of the
lung
. and perfusing the remaining lung with the entire cardiac output. The
Q lym increased but L/P decreased, indicating that increased blood velocity
produced hydrostatic rather than permeability edema. Therefore increased
blood velocity and increased wall shear stress can be ruled out as causes of
the increased permeability associated with microembolization.
2. Microvascular pressure
A hemodynamically induced increase in capillary pressure can increase

endothelial permeability to macromolecules (139, 165). Shirley et al. (458)
used dextrans of known particle size and showed that only small-molecular-
weight dextrans escaped from the bloodstream at normal blood volumes; the
larger particles were lost from the blood and appeared in the lymph when
blood volume was increased. Schneeberger (446) observed alterations in in-
terendothelial junctions in the mouse lung after injection of saline in a
1140 ASRAR B. MALIK Vdum 63
volume of 0.5 ml with horseradish peroxidase (Mr 40,000). The tracer passed
rapidly between the endothelial cells of pulmonary capillaries with this vol-
ume but not with a volume of 0.1 ml. Fishman and Pietra (140) observed that
raising Pla to 30 mmHg in isolated and perfused lungs produced a pressure-
dependent leakage of both horseradish peroxidase and hemoglobin into the
interstitium; however, this may reflect a fragile, isolated lung preparation
in which the endothelium may have been injured before the pressure ele-
vation (68). Erdmann et al. (126) found no evidence of increased permeability
in pulmonary vessels at Pla values up to 40 cmHzO with lymph flux data
from intact sheep lungs. One can safely surmise that high Pmv values are
required to produce damage. In the case of the hindlimb, an increased per-
meability was only evident at capillary pressures between 40 and 50 mmHg
(414). The effects of such elevations in pulmonary Pmv have not been ex-
amined in intact animals because it is difficult to maintain adequate blood
flows at the pressure levels required to produce damage.
Although increased pressure could injure the endothelium in the lung,
it is probably not the primary cause of the increased permeability associated
with microembolization: increased permeability was evident even at low Ppa
values (303, 375). Although small pressure elevations are clearly not asso-
ciated with ,endothelial injury in the normal lung (126, 331), the effect of
increased vascular pressures in lungs with an already damaged endothelium
has not been examined.
G. Lymphatic Impairment
Rusznyak et al. (424a) and Staub (470) have outlined the role of the
extensive pulmonary lymphatic system in removing fluid and plasma pro?
teins that leak into the interstitium (354), and Halmagyi (177) has suggested
that lymphatic failure plays a major role in the development of pulmonary
edema. Surgically autotransplanted lungs (95) and lungs in which lymphatics
had been removed (288) became edematous within days, indicating that the
lymphatic loss prevents drainage of interstitial fluid and protein. Systemic
venous hypertension also contributes to pulmonary edema (327), presumably
owing to a decreased pressure gradient for QIYrn into the major veins.
All these factors could operate after microembolization. The pulmonary
lymphatic function could be compromised after microembolisation because
electron-microscopic evidence indicated an accumulation of fibrin within the
alveolar-capillary septum (92, 158). This accumulation may interfere with
uptake of fluid and solutes by lymphatics [i.e., it may cause increased tissue
resistance to QIYm (168, 322)]. Systemic venous hypertension can also occur
as a result of pulmonary vascular obstruction and thus could decrease lymph
drainage because of a smaller pressure head between lymph vessels and
venous outflow. The base-line flow rate of pulmonary flow in sheep is -5 ml/
h (126). A 6-h period of total obstruction would therefore result in a 30-ml
increase in the extravascular fluid volume, which represents only 10% of the
total extravascular fluid volume in a 20-kg sheep lung. Thus complete ob-
struction of the lymphatics would produce only slight interstitial edema
within 6 h and cannot explain the near doubling of extravascular water
content within l-2 h after microembolization in dogs (295, 302).
H. Eflects of Regional Atelectasis
Regional atelectasis occurs after pulmonary microembolization as a re-

sult of airway closure and surfactant loss (468). Pang et al. (387) observed
that atelectasis reduced the degree of edema formation in the lung. The
decreased fluid accumulation was believed to be caused by increased perimi-
crovascular pressure (468). Another consequence of regional atelectasis is
that adjacent normal segments become hyperinflated owing to the inter-
dependent effects (319, 393), and a more negative interstitial hydrostatic
pressure develops. The latter provides a large pressure gradient for fluid
movement into these areas from the adjacent atelectatic segments (387).
Regional fluid shifts in the lung after microembolization have not been ex-
amined, but greater edema may be present in hyperinflated regions than in
the collapsed regions.
I. Cellular and Huwwral Mechanisms
Recent evidence has favored cellular and humoral factors as the me-
diators of the increased vascular permeability and pulmonary edema asso-
ciated with microembolization. Before discussing the specific mediator, it is
important to consider how the mediators reach the sites of fluid exchange
in small pulmonary vessels. Although the sequence of events from mediator
release to endothelial injury is poorly understood, there are three possible
pathways that mediators could utilize to reach the sites of injury in pul-
monary microvessels. First, terminal patent arteries ranging from 200 to
300 pm in diameter give off branches at right angles that form collateral
pathways with downstream microvessels (as shown at left in Fig. 7; 248,249,
254,466). In this way blood flow can persist in these lung segments, and the
putative factors may reach the microvessels despite obstruction of the main
inflow vessels with microemboli. Second, small-molecular-weight factors can
diffuse directly through the lung parenchyma to the nearby patent micro-
vessels; therefore the adjacent vessels rather. than the obstructed vessels
may be the primary sites of the increase in permeability. Third, substances
released into the circulation downstream from the emboli may eventually
be carried to pulmonary microvessels via the bronchial arterial flow. Because
the bronchial and pulmonary vascular beds are connected (56), the putative
factors in the bronchial circulation have a direct access to the pulmonary
circulation.
1142 ASRAR B. MALIK vbluww 63
FIG. 7. Effects of emboli of different sizes on

200Mm Emboli 5OOym Emboli pulmonary microcirculatory hemodynamics. With
microembolus caused by glass beads 200 pm in
diameter (as shown at Z&), collateral vessels al-
low blood flow to persist in downstream lung seg-
ment because of collateral branching pattern.
With macroembolus 500 pm in diameter (shown
at tight), flow is obstructed upstream from point
of vessel collateralization, and flow is diverted
through nonembolized regions of lung. This model
agrees with concepts of Kniseley (248) and Krahl
(254) concerning pulmonary arterial “catch traps”
that allow flow to persist through right-angle col-
lateral vessels. Flow model explains the rapid
lysis of microclots as well as vessel recanalization
after microembolism and provides mechanism by
which subtances released from thrombi, lung tis-
sue, and plasma can increase permeability of
downstream microvessels.
The first of the above mechanisms appears to be the most important

because embolization with glass beads 500 pm in diameter, which presumably
blocks any collateral flow, did not result in an increased pulmonary vascular
permeability (219). Figure 7 compares the consequences of obstruction with
a ZOO-pm embolus with those of obstruction wi th a 5000pm embol us Because
of collate ral flow, downstream m.icrovessels are affected on1.y with th e smaller
embolus. If the other two mechanisms discussed above were as important
as the first, an increase in permeability should have been evident even after
obstruction with the large embolus, but this was not the case (219); therefore
the putative factors must reach the microvessels via collateral branches of
the pulmonary artery.
The following sections .discuss the specific cellular and humoral factors
postulated as either mediators of or factors contributing to the pulmonary
edema associated with the microembolization.
1. Fibrin
Fibrin “plugs” in pulmonary microvessels are usually seen with pul-

monary microembolization that is associated with thrombosis (18, 65, 436-
438). Saldeen (437,438) hypothesized that fibrin entrapment was the factor
primarily responsible for the increased permeability with microembolization
(43). According to Saldeen (437, 438), the generation of fibrin-degradation
products associated with the lysis of intravascular and extravascular fibrin
mediates the endothelial cell injury.
In addition to fibrin thrombi in vessels, fibrin deposits were sometimes
found near the interendothelial junctions and in the perivascular spaces (15).
In a somewhat puzzling observation in lungs obtained from patients who
died from the adult respiratory distress syndrome, Bachofen and Weibel
(18) observed more fibrin in the interstitium than in the blood vessels. Rather
than indicating a peculiar affinity of the interstitium for fibrin, this differ-
ence may reflect differences in the ability of the luminal and abluminal
endothelial surfaces to lyse fibrin via the fibrinolytic system (418). The fol-
lowing sections review the evidence in support of the hypothesis that fibrin
entrapment mediates increased permeability.
a) Efects of defibrinogenation and heparin. Because fibrin clots have
been implicated in the development of microembolization-induced edema
(43’7; 438), several studies have examined the effects of fibrinogen depletion
and intravascular coagulation inhibition on this phenomenon. Busch et al.
(59) observed in dogs that defibrinogenation, which was produced with a
purified extract of Malayan pit viper venom (Ancrod; 31,408), prevented the
increase in lung weight associated with thrombin infusion. These data do
not directly support the role of fibrin in edema formation because thrombin
cannot produce intravascular thrombi without fibrinogen. Thus the absence
of pulmonary edema in the defibrinogenated dogs may only reflect the ab-
sence of microemboli. To substantiate this interpretation, Malik et al. (298)
demonstrated in defibrinogenated sheep that thrombin infusion failed to
increase Ppa and PVR as well as Qlym and transvascular protein clearance.
Therefore the protective effect of defibrinogenation in preventing increased
permeability appears to be a result of the inability of thrombin to produce
the microemboli rather than the result of any protective effect of defibri-
nogenation per se.
Johnson and Malik (217) repeated Busch’s study (59) in dogs but pro-
duced emboli with glass beads. Glass beads not only produced a permanent
obstruction of pulmonary microvessels but also activated the intrinsic co-
agulation cascade by a direct activation of factor XII (236, 237). Defibrino-
genation prevented the pulmonary edema after glass-bead microemboliza-
tion (217), indicating that the edema was the direct result of activation of
intravascular coagulation and that it was not caused by obstruction of pul-
monary vessels. Heparin pretreatment in dogs also prevented the pulmonary
edema associated with glass-bead microembolization (148, 302). Beyond the
inference that intravascular coagulation plays a role in mediating edema
formation, these studies are not proof of the direct and primary role of
fibrin, because defibrinogenation and anticoagulation prevent both the for-
mation of fibrin microemboli and the subsequent fibrinolysis by plasmin (EC
3.4.21.7) (77,161,237,417). Therefore the inhibition of plasmin synthesis and
the resultant failure to activate the complement system may well have
brought about the protective effects of defibrinogenation or heparin pre-
treatment (127, 237). Because leukocyte margination in the pulmonary mi-
crocirculation may not occur without complement activation (96, 97, 212),
the absence of edema could reflect a lack of leukocyte activation rather than
a direct protective effect of defibrinogenation or heparin. Another criticism
of this work in dogs is that lung vascular permeability was not assessed.
The protective effect of heparin or defibrinogenation seen in dog lungs
1144 ASRAR B. MALIK Vdume 63
(217,302) is not reproducible in the sheep preparation (37). Binder et al. (37)
showed that neither defibrinogenation nor heparin pretreatment prevented
the increased Qlym and transvascular protein clearance observed after glass-
bead microembolization. The major difference in protocol was the use of
siliconized glass beads in the sheep studies (37). Johnson and Malik (ZZOa),
however, repeated Binder’s study in sheep and used nonsiliconized beads;
and they obtained the same results. It is more likely that species differences
exist relative to the coagulation and fibrinolytic systems (9, 116, 151). Fi-
brinolytic activity in dog lung is much greater than that of sheep lung (9,
151) because fibrinolysis in dogs must be inhibited with tranexamic acid or
aminocaproic acid to induce microembolization after thrombin; this step is
not necessary in sheep (9, 300). Therefore, for a given degree of pulmonary
vascular thrombosis, the more potent fibrinolytic mechanism in dogs is ex-
pected to generate a greater increase in plasmin activity and in local levels
of fibrin-degradation products, and therefore these products are more likely
to produce injury of the dog pulmonary endothelium.
The experiments involving heparin and defibrinogenation must be
treated cautiously because the effects of heparin and defibrinogenation on
fluid accumulation in the lung are more complex than was previously thought
(30,216). Heparin pretreatment of dogs did not prevent the pulmonary edema
induced by alloxan, but the edema was greater (323). Some researchers have
suggested that fibrin in the interstitium of nonheparinized dogs prevented
fluid accumulation by decreasing the available interstitial volume (323,486).
In addition a recent study by Carr (66) has shown that heparin given in-
travenously at dosages of 50-100 units/kg suppresses in skin the increased
vascular permeability induced by histamine, bradykinin, or prostaglandin
Ez (PGE2). Thus the protective antipermeability effect of heparin may be
independent of its anticoagulant properties.
b) Fibrin-degmdatim pod~~ti. Fibrin-degradation products have been
proposed as the primary mediators of the increased permeability associated
with microembolization (278, 437, 438). Several experiments point to their
importance. The increased vascular permeability observed after thrombin-
induced pulmonary microembolization is associated with the generation of
fibrin-degradation products (221). Embolization with fibrin microaggregates,
which do not activate intravascular coagulation or fibrinolysis (221), resulted
in the filtration of protein-poor fluid (i.e., a decrease in L/P). The concen-
tration of fibrin-degradation products did not increase to the same extent
after injection of fibrin microaggregates, whereas the changes in leukocyte
and platelet counts were comparable (221). Therefore the appearance of fi-
brin-degradation products correlates well with the time course of the in-
creased pulmonary vascular permeability, although the causal relationship
between fibrin-degradation products and increased permeability has not been
established.
Evidence also indicates that fibrin-degradation products of several dif-
ferent molecular weights increase vascular permeability (37, 438). Saldeen
(438) has isolated a pentapeptide (Ala-Arg-Pro-Ala-Lys) originating from

the NH&erminal portion of the p-chain of fibrinogen and an undecapeptide
(Ser-Gln-Leu-Gln-Lys-Val-Pro-Pro-Glu-Trp-Lys) originating from the mid-
section of the a-chain of fibrinogen; both these compounds increased ma-
cromoleculer permeability in the microvessels of hamster cheek pouch. How-
ever, the effects of these peptides on pulmonary vascular permeability has
not been examined. Studies by Curreri and co-workers (284, 306, 307) have
demonstrated that fragment D, a primary fibrin-degradation product, pro-
duced interstitial edema and alveolar hemorrhage when infused into rabbits.
These changes were attributed to an increased capillary permeability to
plasma proteins because greater amounts of labeled albumin accumulated
in the extravascular space after the fragment D challenge. The effect of
fragment D was specific because fragment E infusion did not evoke the same
response (306). Possibly platelet aggregation rather than fragment D per se
was responsible for the fluid accumulation and capillary leak in this study
because the rabbits became thrombocytopenic during the infusion process
(306). The finding that a histamine 1 (HI) blocker, diphenhydramine, pre-
vented the pulmonary edema after fragment D infusion also suggests a role
for histamine (306), which is known to be released in large amounts after
aggregation of rabbit platelets (116). Fibrin-degradation products ranging
from 15,000-25,000 iW” have also been reported to increase the permeability
of macromolecules in rabbit skin vessels (479). Therefore, even though fibrin-
degradation products of varying values of molecular weight are apparently
capable of altering endothelial integrity, investigators have not yet deter-
mined whether these products are responsible for the changes observed in
lungs after microembolization.
The mechanism by which these fibrin-degradation products increase
vascular permeability to macromolecules is also unknown. Like other me-
diators of inflammation (such as bradykinin and histamine), they appear to
cause endothelial cell contraction (233). A normal monolayer of cultured
endothelial cells became rapidly disorganized after layering fibrin clots on
the cells (98). The effect was’ reversed after removing the clots. Other cell
types did not exhibit the same changes when exposed to fibrin (98), indicating
that fibrin and/or its products have specific actions on endothelial cells.
Fibrin-degradation products could also induce pulmonary leukostasis be-
cause they are known to be leukotactic substances (243,479)..The increased
permeability seen with fibrin or its products may simply represent release
of toxic substances, such as oxygen radicals and proteases, by activated leu-
kocytes (290). In addition to direct and leukotactic effects, fibrin-degradation
products may cause the release of other mediators such as histamine (306),
which may then alter pulmonary vascular permeability.
c) FibrinoZysti. Because fibrin-degradation products have been reported
to mediate pulmonary edema associated with microembolization (437, 438),
the rate at which fibrinolysis occurs should be related to the degree of edema.
Fibrinolysis is particularly important in the pulmonary circulation because
1146 ASRAR B. MALIK Volume 63
pulmonary endothelial cells, like those of cerebral and coronary vessels, pos-
sess abundant amounts of tissue plasm inogen activator (417,497,526), which
converts plasminogen to plasmin, the potent serine protease (237, 41.7). The
finding that most fibr in was cleared from rabbit, rat, and dog lungs wi thin
1 h after intravascular coagulation is a measure of the remarkable ability
of the pulmonary fibrinolytic system (60, 61, 295, 434).
The role of fibrinolysis in the pulmonary edema formation associated
with microemboli has been studied by inhibiting fibrinolysis with either
tranexamic acid or e-aminocaproic acid (418). This caused greater fibrin de-
position and a greater amount of pulmonary edema (59,295,300), suggesting
that depression of fibrinolytic activity enhances the amount of edema for-
mation. Because pulmonary vascular resistance did not increase after ad-
ministration of the tranexamic acid, the results could not be explained by
more vascular obstruction caused by fibrin entrapment (295).
Saldeen and co-workers (280,281,438) suggested that the edema formed
after inhibition of fibrinolysis is mediated by a gradual gen erati on of fibrin-
degradation products in embolized regions. This assumes that fibrinolysis
is not completely inhi .bited and that a small amou nt of the degradation
products continuously enters the microcirculation. Nevertheless this hy-
pothesis should be tested by comparing the effects of complete versus in-
complete fibrinolysis inhibition. When fibrinolysis was completely inhibited
in sheep (i.e., when generation of fibrin-degradation products is prevented),
thrombin failed to incre Nase lung vascu lar permeability (221a), supporting
the notion that gradual generation of fibr in-degradation products is nec-
essary.
Unlike complete inhibition, microemboli-induced pulmonary edema can
be enhanced by partial inhibition of fibrinolysis (59, 295, 300). The same
effect of partial inhibition can also occur spontaneously after microembo-
lization (277,279,437,438). Inhibition of fibrinolysis occurring over a period
of several days has been proposed as a mechanism responsible for the delayed
edema developing in patients after pulmonary thromboembolism (279, 336,
437, 438) and in dogs after thrombin injection (277, 437). The inhibitor is a
stable ae-globulin that binds to both plasminogen and plasmin in vitro (438),
suggesting that it acts by competing with the plasminogen activator for the
binding sites on plasmi .nogen and plasmin. Circulating free fatty acids appear
to regulate the synthesis of this inhibitor because the increased levels of
free fatty acid caused by norepinephrine administration raised the inhibitor
levels (438). Conversely, decreasing the levels of free fatty acid by nicotinic
acid administration prevented the increase in inhibitor activity (438). The
inhibitor is synthesized in the liver because fibrinolytic activity did not in-
crease after thrombin injection in hepatectomized rats (438). The findi WV
that spontaneous and pharmacological partial inhibition of fibrinolysis re-
sulted in pulm .onary edema support the hypothesis that fibrinoly tic acti vity
.
modulates the degree of edema, perhaps by control .ling the local concen tra-
tions of fibrin-degradation products in the pulmonary microcirculation.
d) Fibrinopeptides. Other potentially injurious factors released during

fibrin deposition are fibrinopeptides A and B, which contain peptides having
16 and 14 amino acids, respectively (25, 365). These peptides are liberated
from fibrinogen when it is converted to fibrin by the action of thrombin (379).
Bayley et al. (27) demonstrated that bovine fibrinopeptide B and human
fibrinopeptide A injected into dogs, rabbits, and lambs caused a decreased
lung compliance and an increased resistance in airways and pulmonary ves-
sels; bovine fibrinopeptide A, however, did not have these effects. Although
fibrinopeptides have not been investigated relative to lung fluid balance, they
increase endothelial permeability of systemic microvessels (91). This per-
meability-increasing effect of fibrinopeptides may be indirect, because fi-
brinopeptides enhance the edemagenic effects of bradykinin (290, 142) and
also cause chemotaxis of leukocytes (290).
2. Pulmonary leukostasis
Sequestration of leukocytes in the pulmonary circulation has been im-

plicated as another primary factor in the development of lung vascular injury
(96, 97, i42, 195, 211, 218, 407). Embolization of rabbit lung with autologous
leukocytes produced pulmonary vascular lesions that were characterized by
constriction of pulmonary arteries, endothelial swelling, and periarterial
infiltration of polymorphonuclear leukocytes (6). In studies conducted in
sheep, lung vascular permeability to proteins was increased after pulmonary
leukostasis induced by infusion of zymosan-activated plasma (96, 97). Zy-
mosan activates the complement system and causes the generation of leu-
kotactic fragments, the most potent being the complement fragment C5a
(96, 97). Either leukocyte or complement depletion prevented the perme-
ability-increasing effect of zymosan-activated plasma (96, 97).
Complement activation and the resultant generation of C5a appears to
be a necessary step for pulmonary leukostasis (127, 312, 424). Polymorpho-
nuclear leukocytes are attracted into the air space after instillation of C5a
into airways either by a direct chemotactic action or by production of another
chemotactic factor from pulmonary macrophages (146). Moreover the infu-
sion of C5a into mice increased the pulmonary microvessel permeability to
proteins, and neutropenia prevented the increased permeability (199), in-
dicating that the response depends on the neutrophils.
The pathway by which C5a is generated after pulmonary microembo-
lization is not known. The most likely mechanism of C5a generation is via
activation of the coagulation and fibrinolytic cascades that occur after pul-
monary embolism (236, 237). Both thrombin and plasmin (which are acti-
vated during intravascular coagulation and fibrinolysis, respectively) have
proteolytic activities (236,237) and thus can cleave the complement proteins.
Plasmin is probably more important than thrombin in complement activa-
tion, however, because lung vascular injury did not occur after thrombin
1148 ASRAR B.MALIK Vohrne 6.9
infusion in defibrinogenated sheep (221a). Therefore thrombin per se does

not cause the injury; rather the deposition of fibrin and subsequent fibri-
nolysis are required.
Although the evidence presented above implicates leukocytes in lung
vascular injury, the question remains -are leukocytes necessary for the in-
creased pulmonary vascular permeability and edema associated with mi-
croembolization? When leukocytes were depleted by nitrogen mustard (142)
or when granulocytes were depleted by hydroxyurea (22), either transvas-
cul .ar pro ltein clearance did not increase or the increase was attenuated after
pulmonary microembolization (22, 142). Depletion of granulocytes by hy-
droxyurea also prevented the increase in extravascular lung water content
observed after glass-bead microembolization (218). The effects of granulo-
cytopenia have been further examined after thrombin (483a), a model known
to induce intravascular coagulation and to activate the complement system
(294). In this study, neither Qlyrn nor L/P changed after embolization in
granulocytopenic sheep, whereas QIYrn increased and L/P was unchanged in
control sheep that were embolized to the same degree. Raising the Pla in
the granulocytopenic group after thrombin infusion further increased Qlym
but decreased L/P (Fig. 8), whereas the increase in Qlym after thrombin
administration in control animals was associated with an unchanged L/P
(Fig. 8). The slope of the &, vs. L/P line in the granulocytopenic group was
not different from the slope in normal animals after left atria1 hypertension
(Fig. 8). These studies indicate a protective effect of granulocyte depletion
in preventing the increased permeability. Lung vascular injury associated
with microembolization may be similar to the injury seen with endotoxemia
(186), O2 toxicity (98,146), and acute pancreatitis (483) because these patho-
logical states are also dependenton the presence of white blood cells.
Treatment of leukocytes with cytochalasin B, which causes them to
round up and retract their pseudopodia, minimizes their ability to adhere
to vascular walls and to release superoxide anions (431, 560). In such cases
endothelial damage did not occur (560). Therefore vessel wall adherence must
be another step necessary for the development of pulmonary endothelial
injury associated with leukocytes.
a) A4echantim of leuhxxyte-mediated 1) PROTEASES. The intra-
venous injection of leukocytes produced both lung endothelial lesions (6) and
basement membrane changes (215), suggesti ng that lysosom al enzymes I re-
leased from leukocytes trapped within the lung contribute to lung vascular
injury. The release of proteases from polymorphonuclear neutrophils is be-
lieved to occur during phagocytosis (533,535), and release may be pronounced
when large numbers of neutrophils are trapped in the pulmonary circulation
after embolization. The major enzymes released are neutral proteases, col-
lagenase (EC 3.4.24.3), elastase (EC 3.4.21.11), and cathepsin G (EC 3.4.21.20)
(535). The release of proteases is mediated via the activation of the alternate
complement pathway (115), which may occur after the microemboli-induced
coagulation process. A ntiproteases failed to protect against the immune com-
0.9-
0.8-
0.7-
0
P
aa 0.8-
0,
z
OS-
0.4-
5 15 20
PULMONARY LYMPH FLOW ( ml I hr )
FIG. 8. Relationship between pulmonary lymph flow and ratio of lymph-to-plasma protein
concentration (L/P) after raising pulmonary microvascular pressure (Pmv) by inflation of left
atria1 balloon. Responses are shown for normal lungs, for lungs after embolization with throm-
bin, and for lungs after embolization with thrombin in granulocyte-depleted sheep. In normal
lungs, L/P decreased after raising Pmv; however, L/P did not decrease when Pmv was increased
after thrombin. Raising Pmv in granulocyte-depleted group after thrombin administration re-
sulted in increase in lymph flow and associated decrease in L/P. The latter changes were con-
sistent with normal sieving of proteins in these lungs and differed from increased microvascular
permeability to proteins evident in untreated animals after thrombin administration.
plex-mediated lung vascular injury, whereas superoxide dismutase (EC

1X.1.1) completely prevented the injury (224), indicating the importance of
superoxide anions rather than proteases. The release of myeloperoxidase
from polymorphonuclear sites triggered by C5a was minimal, and no cor-
relation existed between the degree of myeloperoxidase release and the ex-
tent of endothelial damage in cultured endothelial cells (431). These obser-
vations suggest that this enzyme is not a factor in the genesis of vascular
injury. ,
II) SUPEROXIDE ANIONS. Sacks et al. (431), McCord and co-workers (395,
439), and Del Maestro et al. (113) have suggested that leukocytes injure the
microvessels primarily by the production of superoxide anions during bursts
of metabolic activity associated with phagocytosis. The pathways of O2 re-
duction are shown in Figure 9 (147, 395).
It is well established that oxygen radicals serve a bactericidal role (147,
395); however, the concept that oxygen radicals are important in the patho-
genesis of endothelial cell damage is relatively new. In a preliminary report,
Flick et al. (141) showed that superoxide dismutase, which protects against
deleterious actions of the oxygen radical 0; on cell walls by catalyzing its
1150 ASRAR B. MALIK vi.&mte 6.9
e- e- + 2H+
02 - 02- .“202.22GTo”.z,
H20 H20
02 - + 02 -+ 2H+ - Hz02 + 02 Superoxide dismutases
H202 + Hz02 2H20 + 02 Catalases
H202 + RH2 t 2H20+R Peroxidases
FIG. 9. Univalent pathways of oxygen reduction and enzymatic defenses against the oxygen
radicals OH l , 02, and H202. [From Fridovich (147).]
dismutation to Hz02 and 02, prevented the increase in transvascular protein

clearance associated with air embolization (Fig. 9). However, superoxide
dismutase was protective only when it was combined with heparin (141). The
reason for this unusual action of heparin is unclear, but the finding nev-
ertheless suggests that 02 contributes to the microemboli-induced increase
in lung vascular permeability.
Another toxic species, H202, is normally removed by catalase, which
converts it to HZ0 and 02, and by peroxidase (EC 1.11.1.7), which reduces
it to HZ0 (Fig. 9). If the first two intermediates of O2 reduction, 0, and,HzOz,
are effectively removed, the formation of a third potentially more toxic spe-
cies, the hydroxyl radical OH. [generated by the Haber-Weiss reaction 0,
+ H202 4 O2 + OH. t OH- (147)] is preventable because the Haber-Weiss
reaction depends on 0, + H202 substrates. Because of the potential of gen-
eration of these toxic oxygen radicals, there is a need to determine the
relative contributions of 02, H202, and OH in mediating lung vascular
l
injury after microembolization.

The enzyme responsible for superoxide production by neutrophils is the
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase located
within the membrane of the cells (16,313,318). This enzyme oxidizes NADPH
on the cytoplasmic side and converts O2 to 0, on the-exterior surface of the
membrane (16,313,318). Therefore most of the 0, is produced on the exterior
plasma membrane (147,313), where there is little or no superoxide dismutase,
and thus may injure endothelial cells if produced in large quantities.
Superoxide anions (OS, H202, and OH.) interact directly with tissue
components by oxidizing or reducing the structurally important tissue ele-
ments such as cell walls (147). In the intracellular environment, the level
of 0, and H202 are controlled by superoxide dismutase, catalase, and per-
oxidase (147, 314). Because these enzymes are not normally present in any
appreciable quantities in the extracellular space, the rapid generation of
02 or H202 into the extracellular fluid may be an important determinant of
lung vascular injury.
There is ample evidence that superoxide anions injure cell membranes
when their local concentrations are not reduced by scavenger enzymes such
July 1983 PULMONARYMICROEMBOLISM 1151
as superoxide dismutase or catalase (EC 1.11.1.6). The instillation into rat

lungs of xanthine and xanthine oxidase (EC 1.2.3.2), which generate super-
oxide anions, produced acute pulmonary injury (223). The injury was pre-
vented in the presence of superoxide dismutase (223), which indicates that
the injury is the result of 02 generation.
The causative factor for the production of 0, by leukocytes is not known.
Superoxide production may occur by the direct action of C5a (19,313) or by
the action of serine proteases such as plasmin (247). Administration of C5a
or plasmin in vitro caused the generation of 0; by polymorphonuclear leu-
kocytes, and the effect of plasmin was inhibited by serine protease inhibitors
(247). Because both C5a and plasmin are generated after microembolization
as a res ult of complement and coagulation activation, they may be important
factors in mi croembolism-ind uced lung vascular injury. Therefore plasmin
activation and the generation of C5a appear to be important not only in
leukocyte margination after microembolism but also in leukocyte activation
and generation of superoxide anions.
III) OTHER MECHANISMS. Leukocyte-mediated endothelial injury may
also cause release of vasoactive hormones such as histamine from basophils
(46,163). However, histamine does not produce a large increase in pulmonary
vascular permeability (53). A lso the increased permeability induced by glass-
bead microembolization was unaltered with a ntihistamines (257), indicating
the relative unimportance of histamine.
Finally, leukocytes are often seen between endothelial cells and the base-
ment membrane and even between the interendothelial junctions, probably
caught in the process of transmigration (527). Because they can migrate into
these strategic sites, any alterations in leukocyte shape that are due to swell-
ing or shrinkage may mechanically disrupt the junctions and increase the
permeability of the vessels to fluid and macromolecules.
IV) LEUKOCYTE-PROSTAGLANDININTERACTION. Prostaglandins are active
participants in the inflammatory response of leukocytes in the systemic
microcirculation. Wedmore and Williams (527) have formulated a two-me-
diator hypothesis to explain the leukocyte-mediated permeability increase
of skin blood vessels. The first mediator, probably C5a, increased vascular
permeability by inducing leukostasis and leukocyte activation. The second
mediator produced by endothelial cell membranes, either prostacyclin [pros-
taglandin I2 (PG12)] or PGE2, potentiated the plasma protein leakage by
inducing relaxation of arteriolar smooth muscle and thereby increasing cap-
illary pressure (253, 527). Little protein exudation was observed when pros-
taglandin synthesis was inhibited with indomethacin (256). This was ex-
plained by the fact that synthesis of PG12 and PGEz was inhibited and no
vasodilation occurred. Prostaglandins may interact in a similar fashion in
the pulmonary microcirculation because inhibition of prostaglandin synthe-
sis with indomethacin or ketoprofen prevented the thrombin-induced in-
creases in pulmonary vascular permeability (514). It is difficult, however, to
reconcile the reported enhancement of the leukocyte-mediated inflammatory
1152 ASRAR B.MALIK Vohme 63
response by PG12 or PGE2, because the same prostaglandins depress leu-

kocyte chemotaxis (369).
A more likely mechanism by which prostaglandins contribute to the
leukocyte-dependent increase in lung vascular permeability may be by the
ability of some eicosanoids such as TXA2 to induce leukocyte adherence and
aggregation (466a). Garcia-Szabo et al. (15la) recently observed that inhi-
bition of TXA2 generation prevented the thrombin-induced increase in lung
vascular permeability as well as the immediate decrease in leukocyte count
that occurred with thrombin. This observation supports the notion that TXA2
interacts with leukocytes and thereby plays a permissive role in the devel-
opment of lung vascular injury after intravascular coagulation.
The specific roles of prostaglandins, thromboxanes, and leukotrienes in
pulmonary edema after microembolism are discussed in section 11114.
V) EFFECTS OF CORTICOSTEROIDS. In vitro granulocyte aggregation in-
duced by zymosan-activated plasma was inhibited by methylprednisolone
and hydrocortisone but not by dexamethasone (180). This was also true after
leukocyte aggregation induced in vivo by injection of zymosan-activated
plasma or endotoxin (20,179,180). The disaggregating effect of steroids was
nonspecific because the effect of other leukotactic agents, N-formyl-Meth-
Leu-Phe and ionophore A23187, was also inhibited by methylprednisolone
(180, 462). Corticosteroids may disaggregate granulocytes by an effect on
receptor sites because methylprednisolone has been shown to inhibit the
binding of the chemotactic peptide N-formyl-Meth-Leu-Phe to the granu-
locyte receptors (180, 462).
Methylprednisolone pretreatment or treatment soon after challenge of
sheep with Escherichia coli (E. COZQendotoxin prevented increased vascular
permeability, as measured by lack of increases in Qlym and transvascular
protein clearance (52). Because studies of granulocyte depletion indicated
that the increased permeability with endotoxemia is mediated by granulo-
cytes (186), corticosteroids may act by inhibiting granulocyte aggrega-
tion (180). The effects of methylprednisolone on the increase in lung vascular
permeability and on the pulmonary leukostasis after pulmonary microem-
bolism have not been examined.
VI) LEUKOCYTE-FIBRIN INTERACTION. Granulocyte removal and fibrino-
gen depletion prevented pulmonary edema formation after glass-bead mi-
croembolization in dogs (217, 218). The question arises whether fibrin en-
trapment and pulmonary leukostasis are related, because both appear to be
necessary for pulmonary edema development. As shown in Figure 10, fibrin
entrapment may be coupled to leukocyte mobilization and activation. Intra-
vascular fibrin results in the activation of plasminogen and its conversion
to plasmin, which activates the Hageman factor (factor XII) in plasma (236,
237, 341). The activated Hageman factor initiates the intrinsic coagulation,
fibrinolytic, and complement-system activation; therefore the consequent
generation of the chemotactic factor C5a is linked to the clotting mechanism.
Plasmin can also directly activate the complement system independently of
t
PLATELET - Complement w
THROMBIN -e . .
AGGREGATION Act,v>~osTAs’s
Fibrinogen e FIBRINe FDP
I
Plasminogen
Activator
Plasminogen ’ w Plasmin
FIG. 10. Consequences of thrombin-induced microembolization. Thrombin activates platelet

aggregation, polymerizes fibrin, and activates the complement system directly by proteolytic
cleavage and indirectly by activation of plasmin. Pulmonary leukostasis secondary to intra-
vascular coagulation may occur by 3 mechanisms: 1) generation of chemotactic fragments (e.g.,
C5a) after complement activation, 2) entrapment of leukocytes in fibrin meshwork, and 8) che-
motactic effects of generation of fibrin-degradation products secondary to plasmin-induced fi-
brinolysis.
Hageman factor (Fig. 10; 237). Fibrin-degradation products produced as a

consequence of plasmin-induced fibrinolysis are also chemotactic for leu-
kocytes (243, 479). Moreover the fibrin meshwork immobilizes granulocytes
within intravascular thrombi and enhances their contact with the vessel
wall (453). Thus intravascular coagulation is an important step in initiation
as well as in amplification of the leukocyte-mediated pulmonary vascular
injury.
Leukocyte activation may in turn lead to further intravascular coagu-
lation, because the release of lysosomal enzymes from leukocytes activates
clotting factors (162,187). In addition leukocyte-mediated endothelial injury
results in the release of tissue thromboplastin due to cellular injury, which
then activates the extrinsic coagulation (thromboplastin-dependent) cascade
(236, 237), and the exposed collagen substratum activates the intrinsic co-
agulation (Hageman factor-dependent) cascade (236, 237). Leukopenia in-
duced by nitrogen mustard prevented the entrapment of fibrin (368), sup-
porting the hypothesis that fibrin deposition also occurs as a direct result
of leukocytes. Therefore activation of the clotting cascade produces pulmo-
nary leukostasis, and leukocyte activation can produce intravascular coag-
ulation; as a consequence a positive-feedback system is initiated.
These different interactions between leukocytes and intravascular co-
agulation explain why both defibrinogenation and leukopenia protected
against the microvascular damage associated with microembolization in dogs
(217, 218).
1154 ASRAR B. MALE vohrne 6.9
3. Platelet aggregation
The factors that cause platelet aggregation are summarized in Figure

11. These are: 1) the activation of thrombin (193, 507), 2) the release of
adenosine diphosphate (ADP) from injured endothelial cells (534), and 3)
the exposure of the subendothelial collagen after vessel injury (185, 534).
However, the role of platelet aggregation in mediating the increased pul-
monary vascular permeability after embolization is probably minor. Collagen
fibrils were injected into rabbit lungs to induce platelet aggregation; the
result was only a 20% increase in fluid filtration that lasted 30 min (510).
Increased filtration was prevented by perfusing the lungs with a platelet-
deficient plasma before the collagen injection (510), indicating that the small
transient increase on filtration is dependent on platelets.
The effect of platelet aggregation on the change in lung vascular per-
meability was examined in sheep by determining the relationship between
ADP-induced platelet aggregation and lung fluid balance (333). In these ex-
periments, Qlym increased by 30% and the L/P did not change from base line
after the ADP injection. As shown in Figure 12, the small filtration increase
was not caused by increased endothelial permeability to plasma proteins,
because an increase in Pmv produced an increased Qlyrn but decreased L/P,
a finding consistent with hydrostatic edema. Therefore platelet aggregation
per se does not seem to increase pulmonary vascular permeability to proteins,
ruling it out as a major factor in initiating the increase in vascular per-
meability associated with microembolization.
The role of platelets after microembolization has been examined by
depleting platelets in dogs (59, 436) and sheep (36) with antiplatelet serum
and then studying the response of the endothelium. Platelet depletion pre-
vented neither the pulmonary edema (59) nor the increased pulmonary vas-
cular permeability (36) associated with microembolization, indicating that
the increased permeability and edema occur independently of platelets.
There is a prevalent hypothesis that platelets support the integrity of
the vasculature by forming “plugs” that close large gaps that develop in the
endothelial lining of the capillary wall (106, 107). Petechiae and purpuric
hemorrhages that characterize thrombocytopenia have been explained by
postulating that large openings occur in the vasculature when platelet num-
bers are low (156). Roy and Djerassi (423) demonstrated an increased number
of red blood cells in thoracic duct lymph after thrombocytopenia and a re-
duced number when small amounts of platelets were infused. In fact the
amount infused did not appreciably increase the circulating platelet count
(423). Dannelli (107) observed that the rate of edema formation decreased
when frog hindlimb was perfused with a platelet-saline suspension. The
mechanism by which vascular integrity is restored after platelet transfusion
is poorly understood, but platelets may simply plug endothelial gaps, or they
may release mediators that subsequently reduce permeability (106). Visscher
(518) observed that the addition of platelets to the perfusion fluid caused a
PLATELET PLAT ELET
PHOSPHODIESTERASE ADENYLCYCLASE
AMP+ CYCLIC-AMP- A TP
I 1
Pt$ (IN VESSEL WALL)
PHOS PHOLI PID
?TISSUE INJURY-ADP
COAGULATION-
1
‘PGG$H2)bPGE2, PGFza
COLLAGEN I
t
HROMBOXANE A2 -VESSEL
SPASM
(GRANULE RELEASE)
v
MITOGENIC FACTOR
PROTEOLYTIC ENZYMES
PERMEABILITY FACTORS
SEROTONIN
ANTI-HEPARIN
-THROMBOGLOBULIN
B
FIG. 11. Platelets are aggregated secondary to tissue injury resulting in release of adenosine diphosphate (ADP), injury causing release of z
epinephrine, and coagulation-induced by thrombin. Aggregation is amplified after production of thromboxane A2 and release of endogenous ADP
from platelets subsequent to their aggregation. S&d line, inhibitory reaction; AA, arachidonic acid; CO, cyclooxygenase; PG, prostaglandin. Platelet
PGGz as shown or endogenous arachidonic acid causes PGIz (prostacyclin) to be synthesized in endothelium. Platelet aggregation is inhibited by
PGIz because it increases the concentration of platelet cyclic adenosine monophosphate (CAMP). Platelet adhesion occurs after exposure of sub-
endothelium and contact with collagen secondary to endothelial injury. Platelet-release reaction is associated with release of listed factors, some
having potential to increase lung vascular permeability after microembolization. [From Weiss (534).]
1156 ASRAR B. MALIK bhmte 6.9
.90
FIG. 12. Relationship be-

tween pulmonary lymph flow
and ratio of lymph-to-plasma
protein concentration (L/P) af-
ter ADP-induced platelet aggre-
gation @r&en liine with closed
circles). Increased pulmonary
microvascular pressure after in-
flation of left atria1 balloon in-
creased pulmonary lymph flow
but decreased L/P in normal
lungs (broken line with open cir-
.40 I”. ’ I L 1 1 A cles). [From Minnear et al. (333).]
4 6 8 lo 12 14 16 18
Pulmonary lymph flow.
ml / h
persistent loss of weight in isolated and perfused dog lungs. The same effect
could be produced by injecting the supernatant of a platelet suspension (518),
which indicates that a humoral factor was released from the platelets. Se-
rotonin may be this weight-reducing factor, because infusions of low con-
centrations of serotonin into the lung caused a loss in lung weight, whereas
a high concentration (which produces pulmonary hypertension) produced
edema (54, 518). These findings agree with the recent observation of Sweet-
man et al. (481) that serotonin prevented the formation of petechiae in
thrombocytopenic hamster cheek pouch microvessels. If this finding can be
extrapolated to lung tissue, it is possible that platelet serotonin release in-
hibits the development of pulmonary edema by a direct protective effect on
the microvessel endothelium. The other possibility is that serotonin produces
intense precapillary constriction, thereby reducing the edema by decreasing
the filtration pressure
4 Products of amchidonate
a) Prostagkmdins. Prostaglandins of both the E and F series are released

after pulmonary microembolization induced by injection of collagen fibrils
(5,227,282,432,512). The normal pulmonary circulation rapidly inactivates
prostaglandins of the E and F series (138, 398), indicating that these pros-
taglandins must have been generated either in large quantities or distal to
the inactivating mechanisms. Prostaglandins are apparently released as a
nonspecific response to microembolization: increased PGEz concentrations
have been measured in pulmonary venous blood from isolated guinea pig
lungs after embolization with substances as diverse as fat emulsion, micro-
spheres, and colloidal emboli (227,282, 432, 511, 512). The PGEz release per-
sisted when the lungs were perfused with platelet-free plasma (511, 512),
indicating a lung tissue source. However, this finding does not rule out the
generation of prostaglandins from platelets and leukocytes directly embo-
lized in the pulmonary vascular bed (337).
In addition to the classical prostaglandins, TXAz and PG12 are also gen-
erated by the cyclooxygenase pathway (337), as shown in Figure 13. Thrombin
is a potent stimulus for platelet aggregation and leukostasis, which results
in the liberation of TXAz from platelets and possibly from leukocytes as well
as the liberation of PG12 from pulmonary endothelial cells (337). Both TXA2
and PGIz have been detected in pulmonary venous effluent after endotoxemia
(463), cardiopulmonary bypass (176), injection of zymosan-activated plasma
(89), and thrombin-induced pulmonary microembolization (15lb). Thus TXA2
and PGIB release is a nonspecific response to various pulmonary insults.
Bowers et al. (47) have examined the effects of PGE2, PGFz,, and an
cu-methylene ether analogue of endoperoxide (PGH2) on pulmonary fluid and
protein exchange in sheep. These agents caused an increased QIYrn and a
decreased L/P, indicating that these prostaglandins in the normal lung in-
crease Pmv and not microvascular permeability. These findings are consis-
tent with the known pulmonary vasoconstrictor effects of these agents (234).
Infusion of arachidonic acid also increased capillary filtration by increasing
Pmv (374). It appears from these studies that prostaglandins in the normal
lung increase pulmonary vascular pressures but not macromolecule per-
meability.
Prostacyclin (i.e., PG12) caused a dose-dependent increase in Qlym, and
the L/P was unchanged (373). Even though this finding could be interpreted
as representing an increased vascular permeability, it more probably reflects
an increased surface area for vascular exchange, because PGIz is a pulmonary
vasodilator (234). The role of TXA2 has not been examined because it is
degraded within 30 s (337); it is unlikely, however, that TXAz increases mac-
romolecular permeability in the normal lung: ADP-induced platelet aggre-
gation releases TXA2 (337) without any change in lung vascular permeabil-
ity (333).
It is conceivable that prostaglandins affect permeability but only in the
presence of other humoral mediators. This synergistic effect was indicated
by the enhanced leakage of plasma proteins induced by intradermal injec-
tions of bradykinin and histamine in the presence of prostaglandin El (PGE1)
(493). The increased protein movement did not appear to be caused by the
PGE1-induced vasodilation because papaverine did not potentiate edema for-
mation in the presence of bradykinin and histamine (493).
Infusion of PGIz blunted the increased Qlym and protein clearance as-
sociated with endotoxemia (114,372) and with pulmonary microembolization
induced by either air (474) or clots (503). However, these effects do not nec-
essarily represent a protective role for PGIz on permeability, as Demling et
al. (114) have suggested. Infusion of PGIz decreases Ppa (234), and thus the
protective effect is probably the result of a decreased Pmv after embolization.
As discussed in section III..&?UIV, the generation of prostaglandins and

TXAz associated with intravascular coagulation may contribute to the
thrombin-induced increase in lung vascular permeability (38a, 151a, 151b).
The evidence comes from the finding that cyclooxygenase inhibition with
indomethacin or ketoprofen prevented the increased permeability after
thrombin (38a). The protective effect was narrowed to inhibition of TXAz
generation because inhibition of thromboxane synthetase with dazoxiben
(an imidazole derivative) prevented the increased permeability (151a, 151b).
Thromboxane A2 may contribute to the increased permeability by promoting
leukocyte aggregation and adherence (466a). In fact, thromboxane synthetase
also prevented the decrease in leukocyte count after thrombin administration
(151a, 152b), supporting the theory of such TXAz promotion. Therefore TXA2
generation in the presence of pulmonary .leukostasis appears to be an im-
portant determinant of lung vascular injury after microembolization,
whereas TXAz in the normal lung does not appear to produce injury.
b) Leukotrienes. Arachidonic acid released from cellular phospholipids
is metabolized to 5=hydroperoxy=6,8,11,14=eicosatetraenoic acid (50HPETE)
by 5-lipoxygenase (EC 1.13.11.12) and subsequently to the leukotrienes (Fig.
13; 121, 270, 342). Leukotriene A is converted either to B4 or to the slow-
reacting substance of anaphylaxis components, leukotrienes C4 and D4 (121,
270,342). Arachidonic acid can also be metabolized by cyclooxygenase to the
classic prostaglandins, TXAz, and PG12 (121, 342). The factors determining
the dominant pathway for a given condition are unknown.
Leukotrienes, in particular leukotriene B4 and 5-hydroxy=6,8,11,14=ei-
cosatetraenoic acid (50HETE), are potent chemotactic- and leukocyte-ag-
gregating factors (370). These compounds either may have a direct effect or
may increase vascular Pe rmeability indirectly by affecti ,ng th .e white blood
cells. Their effect on lu w!z vascular permeability h as not been S tudied. Leu-
kotriene D4 produces constriction of airways and skin microvessels, and it
appears to be more potent than leukotriene C4 (182). Leukotriene D4 was as
potent as bradykinin on a molar basis in increasing the permeability of skin
vessels of m inea pigs and was 5-100 times more potent than leukotriene Cd.
However, In rat skin vessels, leukotriene D4 was as potent as leukotriene C4
(502). In rabbits, however, nei .ther leuko triene C4 nor D4 increased the per-
meability of skin vessels (502) . Thus the permeability-increasing effects are
species dependent. The comparative effects of the leukotriene series on lung
vascular permeability have not been examined.
The evidence involving leukotrienes in the formation of pulmonary
edema associated with microembolization is at best circumstantial. Ogletree
and Brigham (371) have made the intriguing observation that inhibitors of
the cyclooxygenase system (such as indomethacin and meclofenamate) en-
hanced the pulmonary vascular permeability changes associated with en-
dotoxemia. This finding suggests generation of leukotrienes as the pathway
shifts from the cyclooxygenase system tofthe lipoxygenase system. It is also
possible, however, that PG12 or PGE2 generation normally minimizes the
1160 ASRAR B. MALIK vohne 63
increase in pulmonary microvascular permeability; thus a permeability in-

crease is expected during cyclooxygenase inhibition because synthesis of PGIz
and PGE2 is blocked. Studies in sheep indicate that PGEl blunts the increases
in QIYm and transvascular protein clearance associated with air microem-
bolization (474) and endotoxemia (114, 372), although these effects may be
explained by decrease in capillary pressure rather than by a direct effect on
permeability.
In vitro studies indicated that leukotriene D4 generation from arachi-
donic acid is enhanced by indomethacin and completely reversed by nordi-
hydroguairetic acid or eicosatetraenoic acid, which are nonspecific inhibitors
of the lipoxygenase pathway (370). These findings suggest that leukotriene
production is increased by changing the pathway of arachidonate metabolism
from cyclooxygenase to lipoxygenase, but the direct effect of leukotrienes on
pulmonary endothelial permeability and their role in producing the per-
meability changes associated with microembolism are not known.
5. Serotonin
In 1954 Comroe et al. (88) observed that serotonin is a potent pulmonary

vasoconstrictor and bronchoconstrictor (530). In 1917 Starling and Verney
(469) were the first to appreciate that some substance was inactivated in its
passage through the pulmonary circulation. They found that isolated kidneys
could not be perfused because of intense renal vasoconstriction and embo-
lization unless a heart-lung preparation was inserted into the perfusion cir-
cuit to remove particulate and vasoactive substances. One of these substances
may have been serotonin; it is now known that serotonin is almost completely
inactivated in blood passing through the pulmonary circulation (299).
Serotonin appears in pulmonary venous blood after pulmonary microem-
bolization, indicating either a release from the lungs into the circulation
(171, 554) or an inhibition of its catabolism. The main sources of serotonin
are platelets aggregated in the pulmonary circulation (534) and in i.nterstitial
mast cells (13,363). The effect of serotonin may be species specific: mast cells
in the rat, rabbit, and mouse contain higher concentrations than sheep or
dog mast cells (269).
Evidence obtained from the sheep preparation indicates that serotonin
is not involved in the development of lung vascular injury. Serotonin pro-
duced an increased capillary filtration that was caused by an increased pul-
monary Pmv (529); that is, the increased Qlym was associated with a con-
comitant decrease in L/P. Although serotonin may not increase pulmonary
vascular permeabi .lity, this does not preclude a contribution of serotonin in
edema formation associated with platelet aggregation. Because the lung vas-
cular permeability to proteins is increased after microembolization (303),
any increase of Pmv caused by serotonin enhances fluid movement into tis-
sues and decreases the role of the edema safety factors restricting fluid
accumulation (486).
6. Histamine
Histamine has long been proposed as a possible mediator of lung vas-

cular injury because it is known to increase vascular permeability (44). The
concentration of histamine in the pulmonary venous blood increases after
embolization with thrombi (432). The primary sources of histamine are the
mast cells, which are situated in the perivascular and interstitial spaces of
the lung (13, 363, SO), and the basophils (45) and platelets (534), which are
trapped in pulmonary microvessels after microembolization. The details con-
cerning the degranulation of mast cells are presently not known, but several
factors associated with microembolization c:an cause the release of histamine:
1) mechanical injury (28, 110) [e.g., damage caused by an increase in blood
velocity associated with microembolization (376)], 2) chemical agents (377)
[e.g., the release of cationic proteases after leukocyte activation (405)], 3)
activation of the lipoxygenase pathway (377), and 4) immunological processes
(13, 46) (e.g., complement activation) associated with intravascular coagu-
lation (13, 377).
At doses that did not affect pulmonary hemodynamics, histamine in-
fusion i nto th .e pu .lmonary artery in sheep increased Qlym and protein flux
measurements, suggesting an increased vascular permeability (51, 53). Pre-
treatment with the histamine 1 (HI)-receptor antagonist diphenhydramine
prevented such increases in Qlyrn and protein flux, suggesting that ,a specific
histamine receptor mediated the increased permeability (53). The data in
dogs, however, do not agree with the findings of the sheep lymph studies.
Morphological studies in dogs indicated that histamine acted primarily on
the bronchial venules-the permeability of these vessels to colloidal carbon
increased, whereas the pulmonary vessels were unaffected (396). Drake and
Gabel (118) could not demonstrate that histamine infusion increased pul-
monary microvascular permeability in dog lung preparations. In an attempt
to solve the apparent controversy, Nakahara et al. (355) demonstrated that
histamine infusion . into the bronchi .a1 artery supply of sheep caused increases
in pulmonary Qlym and lYmPh protein flux that were comparable to tho$e
observed after infusion into the pulmon .ary artery, indicating that h istamine
produced the same effect on lungs regardless of its route of infusion. Because
histamine is normally not degraded in its passage through the pulmonary
circulation (432), one possible explanation is that histamine entering the
bronchial arteries caused the increased permeability of bronchial vessels in
sheep. The other possibility is that vascular permeability was not adequately
assessed (488). Raising pulmonary capillary pressure during histamine in-
fusion to assess lung vascular permeability has failed to show a sustained
increase in permeability in sheep (32a, 333a). However, there may well
be a transient increase in lung vascular permeability that has also been
described after histamine infusion in the skel .etal muscl .e vessels (333a).
Another factor weigh .ing heavily aga inst histamine is that it has been
difficult to produce pulmonary edema with histamine, except when it is ad-
1162 ASRAR B. MALIK v&.me 63
ministered in extremely large dosages. [A summary of the negative findings

can be found in the excellent review of Visscher et al. (519).] Moon and
Morgan (338) showed that pulmonary edema in dogs developed only after
administration of 7.5-15.0 mg/kg of histamine twice daily for 9 days. Bariety
and Kohler (25) were able to produce pulmonary edema only when both
histamine (in doses of 0.2-0.5 mg/kg body wt) and epinephrine (0.5 mg/kg
body wt) were administered; histamine given alone was ineffective. Even in
isolated and perfused rat lungs, which are more susceptible to edema (68),
Born (45) was unable to produce pulmonary edema by addition of histamine
to the perfusion fluid. In intact dogs, Pietra and co-workers (396, 397) ob-
served mild interstitial edema after a 190-min infusion of histamine at doses
of 0.7 mg/kg. The increase in extravascular water content in sheep after
histamine infusion averaged only lo-20% after several hours of infusion (396,
397). The variability in the edema response may be related to a variable
constriction of the postcapillary pulmonary vessels (175) and the resulting
lack of change of the capillary pressure in some experiments, which could
minimize the increased fluid accumulation. More probably, however, hista-
mine produces only a trivial *increase in lung vascular permeability.
Pretreatment with diphenhydramine did not prevent increased lung
vascular permeability when pulmonary microembolization was induced by
glass beads (257). This study can be criticized, however, because activation
of the fibrinolytic and complement systems may be necessary for the de-
granulation of mast cells, and the status of these systems after glass-bead
emboli was not assessed. When these systems were activated (e.g., with E.
coli in sheep), diphenhydramine partially prevented the endotoxin-induced
increase in pulmonary vascular permeability (55). If histamine is released
locally after pulmonary microembolization in large quantities (secondary to
activation of coagulation and complement systems), it may similarly con-
tribute to the increased pulmonary vascular permeability after pulmonary
microembolization. Nevertheless this effect, if it does indeed occur, is prob-
ably small and transient.
7. Bradykinin
Bradykinin is generated within the plasma by activation of the intrinsic

coagulation system (409,444). Activation of the Hageman factor (factor XII)
causes the conversion of plasma prekallikrein to kallikrein, which in turn
cleaves circulating plasma kininogen to bradykinin (444). Bradykinin is not
generated in plasma deficient of either prekallikrein or Hageman factor
(444). The pulmonary circulation has an important role in regulating cir-
culating bradykinin concentrations because the converting enzyme, which
is situated at the luminal surface of the pulmonary endothelium, is respon-
sible for bradykinin catabolism (425). Although the converting enzyme is
present on endothelial surfaces of all blood vessels (425,467), the pulmonary
circulation is by far the most important organ system for bradykinin in-
activation, because lungs have a tremendous surface area and receive the
entire cardiac output. Therefore a decreased vascular surface area after
microembolization can impair the inactivation of bradykinin to less vaso-
active products. Decreasing alveolar Po2 (PA%) to levels associated with
arterial partial pressure of O2 (Pas) below 40 mmHg also interferes with
the abil ity of the converting enzyme to inactivate bradykinin and convert
angiotensin I to angiotensin II (467). Decreased surface area and hypoxemia
both’occur after microembolization and thus can potentially decrease the
catabolism of bradykinin, resulting in high circulating levels of this com-
pound.
An extensive literature exists on the role of bradykinin in the inflam-
matory response of systemic vessels (409) [in particular skin vessels (29a)],
but the effect of bradykinin in altering the permeability of pulmonary mi-
crovessels is poorly understood. Morphological studies in dogs indicated that
bradykinin increases the permeability of the bronchial venules (396), but
other studies with dog right lymph duct (which contains a very mixed lymph
consisting of lymph fluid from heart, intestine, and liver) indicated an in-
creased pulmonary Pmv (325). To further confuse the issue, studies in sheep
indicated that bradykinin infusion produces only a small increase in Qlym
with an unchanged L/P (386), although QIYm increased significantly when
hypoxia was induced during the bradykinin infusion. These data suggest an
increased pulmonary endothelial permeability when higher levels of circu-
lating bradykinin were present. However, increased pulmonary Pmv during
bradykinin infusion increased C&m and decreased L/P (33la, 332); such
changes indicate ultrafiltration occurring across normal microvessels rather
than an increased permeability. Also the i nhibiti ,on of the converting enzyme
with captopril in dogs did not produce more edema after glass-bead mi-
croembolization (247a). These findings suggest that higher concentrations
of bradykinin in the pulmonary circulation associated with inhibition of the
converting enzyme do not contribute to the edema.
8. Impaired pulrrumar2/ endothxdial function
a) Alterations in mdzbolic function The pulmonary endothelium is ca-

pable of synthesizing, releasing, and inactivating several vasoactive and per-
meability-increasing mediators that affect lung fluid balance (290, 494). A
complete discussion of these properties is beyond the scope of this review,
although the factors anabolized or catabolized by the pulmonary endothelium
are summarized in Table 2. Any alterations in the concentrations of these
humoral factors resulting from an impairment in endothelial function may
contribute to increased pulmonary vascular permeability and to alterations
in capillary pressure associated with microembolization.
The effectiveness of lung endothelium in performing its metabolic func-
1164 ASRAR B. MALIK Vohm 63
TABLE 2. Handling of vasoactive substances in the pulmonaw vascular bed
I. Metabolized at endothelial surface

Bradykinin-inactivated
Adenine nucleotides (adenosine monophosphate, adenosine triphosphate)-inactivated
Angiotensin I-converted to angiotensin II
II. Metabolized intracellularly
Serotonin
1-Norepinephrine
Prostaglandin E, prostaglandin F, prostaglandin A
III. Synthesized within lung cells
Prostaglandin E and prostaglandin F
Prostaglandin I2
Thromboxane A2
Plasminogen activator
IV. Discharged from intrapulmonary stores
Histamine
Leukotriene B4
Slow-reacting substance of anaphylaxis (leukotrienes C4 and D4)
Kallikreins
tion on biologically active substances is related more to its enormous en-

dothelial surface area and location than to any unique characteristic of the
endothelium (425). Figure 14 shows the metabolic processing of vasoactive
agents. The vasoactive prostaglandins synthesized de novo by the lung en-
dothelium include PGFzc,, PGEz, and PGI,; prostaglandins of the E and F
series are inactivated by conversion to dihydro-15ketoprostaglandin deriv-
atives (337, 425). In addition, lung endothelial cells contain plasminogen
activator, which is capable of initiating fibrinolysis (425, 526, 548). Because
fibrin-degradation products generated by fibrinolysis are believed to con-
tribute to increased lung vascular permeability (438), any alteration in en-
dothelial fibrinolytic activity may thus contribute to the development of
pulmonary edema.
The luminal surface of the endothelial cells is also the site of the con-
verting enzyme responsible for inactivating bradykinin and for converting
angiotensin I to angiotensin II (426). Serotonin, another substance that may
alter lung fluid filtration after microembolization, is also largely inactivated
during a single passage through the pulmonary circuit (229). As previously
discussed, neither bradykinin nor serotonin appears to be a primary mediator
of the increased permeability; nevertheless they may enhance fluid accu-
mulation because of their effects on Pmv and vascular surface area.
b) Changes in ceZZshap. The endothelial monolayer serves as an effective
barrier against fluid accumulation in the interstitial spaces. Alterations in
endothelium shape, which may be related to changes in cell volume (123,
406) and/or to contraction of the intracellular microfilaments (29,555, 562),
can increase the permeability of the microvascular wall to proteins. In ad-
dition, the loss of fibronectin, an adhesive protein that “glues” the endothelial
INTRAVASCUCAR SPACL
saturable, r
L-NE Na* - dependent, L-NE
5-HT carrier -mediated

transport
carrier-mediated,
OH-PG-dehydrogena
7d other enzymes
15 Keto.
Lm13-14dihy&o. I metabo’ites
a
iznverting enzyme
sdykininase
deaminated
dephosphorylated
FIG. 14. Handling of circulating vasoactive substances in pulmonary microcirculation. L-
NE, L-norepinephrine; 5-HT, serotonin; COMT, catechol-O-methytransferase; MAO, monoamine
oxidase; PG, prostaglandin; AI, angiotensin I; AII, angiotensin II; ATP, adenosine triphosphate;
AMP, adenosine monophosphate. Angiotensin-converting enzyme and bradykinase are same
enzyme. [From Junod (ZBa).]
cells to the collagen substratum and maintains cell-to-cell contacts, may also
increase capillary endothelial permeability (49,485,555). The release of pro-
teases from granulocytes causes the breakdown of cell-surface fibronectin
(430). Saba and co-workers (428-430) believe this is an important means of
increasing vascular permeability. Fibronectin administration after pulmo-
nary injury improved cardiopulmonary function, as evidenced by decreased
venous admixture and alveolar dead space (428,429). These findings suggest
fibronectin is important in maintaining the integrity of the pulmonary mi-
crocirculation by promoting the adhesion of endothelial cells to basement
membranes and collagen. An experiment performed by Niehaus et al. (361)
1166 ASRAR B. MALIK i?&mt-e 6.9
supports this hypothesis. In this study the increased QIYrn and protein clear-
ance associated with Pseudomonas sepsis were enhanced. in sheep with fi-
bronectin deficiency. The effect of fibronectin repletion was not studied.
The hypoxemia and loss of essential substrates occurring distal to the

obstruction of pulmonary vessels have been proposed as factors contributing
to the increase in lung vascular permeability associated with emboli (22,
340). Hypoxemia per se cannot be an important factor because decreasing
Paoz in sheep to 40 mmHg did not alter lung vascular permeability to pro-
teins (39).
The decreased substrate delivery, however, appears to be an important
but poorly understood phenomenon associated with endothelial injury. Barie
et al. (22) found that obstruction of one pulmonary artery for 3 h followed
by a 2-h period of reperfusion caused greater edema in ischemic lungs. The
greater edema formation in the ischemic lung could be due to an increased
interstitial protein concentration resulting from the increased microvascular
permeability.
That pulmonary vascular permeability was increased (22,225) after pul-
monary ischemia was also demonstrated in sheep studies (23). Occlusion of
the pulmonary artery for 3 h resulted in steadily increasing Qlym and trans-
vascular protein clearance despite a decrease in the vascular surface area.
The increases in Qlyrn and clearance persisted even after reperfusion (23),
indicating the increased permeability was caused by a period of pulmonary
ischemia rather than by reperfusion per se. The pulmonary vessels and the
coronary vessels behave in a similar manner: coronary vascular occlusion
also increases coronary QIYm and lymph protein concentrations (128).
The edema in the ischemic lung was not related to intravascular co-
agulation and the ensuing microembolization, because the ischemic lung
became edematous even in heparinized animals. Johnson and co-workers
(225) noted that granulocytes marginated in the pulmonary microcirculation,
suggesting their involvement in edema formation after ischemia. Another
possibility is the direct generation of oxygen radicals during ischemia from
the ischemia-induced breakdown of adenosine triphosphate (ATP) to hy-
poxanthine and the conversion of xanthine dehydrogenase (EC 1.2.1.37) to
xanthine oxidase (162a, 313). The reaction between hypoxanthine and xan-
thine oxidase results in the formation of oxygen radicals, which have been
implicated in intestinal vascular injury after intestinal ischemia (162a).
K. Neural Factors
Several studies have examined the role of neural mechanisms in the

development of pulmonary edema after microembolization (231, 232, 460).
Localized pulmonary edema produced by injection of starch suspension into
a pulmonary artery wedge catheter was partially inhibited by the adrenergic

antagonists benanserin and dihydroergotamine (231, 232, 460). The notion
that sympathetics were involved was confirmed by bilateral removal of the
sympathetic chain in dogs (231). The response was largely unaffected by
lysergide, however, suggesting it was not due to serotonin release. When
procaine was injected into the embolized lobe, it also prevented edema in all
lung lobes (232). It was suggested that procaine anesthetized the local end-
organs, which initiated the chain of events leading to edema, but the nature
and site of these receptors were not defined. The decreased water content
of the lung may have been due to a decreased pulmonary Pmv, which can
occur after sympathectomy or procaine injection (104, 206). Edema by neu-
rogenic mechanisms need not be invoked.
The neurogenic theory of pulmonary edema has also been supported by
the finding in dogs that embolization of a lung lobe with a suspension of
starch granules (lo-15 pm in diameter) produced edema not only in the lobe
receiving the emboli but also in the remaining lung lobes (231, 232, 460).
Studies have clearly demonstrated, however, that injection of these emboli
into one lobe does not necessarily rule out emboli entering other parts of
the lung (357). When care is taken to ensure that the emboli do not disperse,
edema develops only in the region of the lung receiving the emboli (263).
L Role of Bronchial Circulation
Because bronchial arteries anastomose with pulmonary microvessels

(56), bronchial blood flow persists through segments of the lung in which
the pulmonary arteries have been obstructed (102). Pulmonary vascular le-
sions and infarctions are more common after obstruction of small pulmonary
arteries than after obstruction of large pulmonary arteries (102). Because
the capacitance of the pulmonary vascular bed distal to the point of ob-
struction is lower after microembolization than after macroembolization,
bronchial blood flow entering the obstructed region results in a greater in-
crease in pressure after microembolization. Figure 15C shows how a greater
rise in pulmonary capillary pressure enhances the degree of filtration in the
segment obstructed in a manner similar to obstruction of a vessel with nor-
mal Ppv (as shown in Fig. 15B). In the model shown in Figure 15, the in-
creased pressure is due to pulmonary venous hypertension, but it could also
occur as a result of obstruction of small pulmonary arteries in which influx
of bronchial blood flow results in a greater increase in capillary pressure
than would occur if the obstruction were in the large pulmonary artery.
M Cellular Edema
Although 65% of the extravascular water content in the lung is contained

within cells, little is known about the factors responsible for cell fluid balance
(465, 489). Endothelial cells represent ~35% of the total cell population of
Pulmomry Arteriole
Broncho-pulmonary
Anaatomoda
- Direction of Blood Flow-

Bronchial Arteriole
CLOT
-Direction of Blood Flow 4

Bronchial At teriole
C Venou8 Pressure
Broncho-pulmonary
- Direction of Blood Flow e

8ronchiol Arteriole
FIG. 15. A: relationship between bronchopulmonary anastomoses and pulmonary micro-

circulation. B: possible sequence of events when pulmonary artery is occluded but without rise
in pressure in occluded segment (e.g., without an increase due to macroembolism or obstruction
of larger pulmonary artery). C embolization of pulmonary artery but with associated rise in
pressure in occluded segment, possibly caused by embolization of microvessels downstream from
more compliant pulmonary arteries or pulmonary venous hypertension. Events in C would lead
to greater edema because of greater rise in capillary pressure in occluded lung segment. [From
Dalen et al. (102).]
the lung (471,489), and a potential exists for considerable fluid accumulation
in these cells. The total amount of free solutes and consequently their osmotic
activity within the cells are regulated by pumps in the membrane. The os-
motic activity difference between cell and environment determines intra-

cellular water content, and any impairment in the function of the Na+-K+
pump determines how much the cell shrinks or swells (287). During hem-
orrhagic shock, the Na+-K+ pump fails because of low O2 availability, and
the result is an increased influx of sodium and water into vascular smooth
muscle (lOO), liver (442,443), and lung cells (421). Moreover, as cell swelling
occurs, a further decrease in O2 consumption occurs (271), causing a further
impairment in the pump function in a positive-feedback fashion. Morpho-
logical evidence indicates that cellular edema is a common feature of pul-
monary vascular injury caused by many different substances (489).
The work of Powers et al. (400) indicates the importance of cells as sites
of fluid accumulation in pulmonary injury. This study shows that mannitol
injection produced a rapid fall in PVR and alveolar dead space and an in-
creased Pa%. Because these changes occurred rapidly and were associated
with decreased plasma sodium concentration, withdrawal of fluid from pul-
monary cells (probably endothelial cells) may be responsible for the in-
creased oxygenation capacity (69,123,464). Although the evidence of cellular
swelling is indirect, it does indicate that cell volume changes should be con-
sidered after microembolization. Mannitol was ineffective in reducing the
pulmonary edema associated with high hydrostatic pressures (411), presum-
ably because the edema was confined to the interstitium.
An important ramification of endothelial swelling is the concept of no
reflow or impaired reflow (143), which refers to reperfusion after stasis or
impaired blood flow. If the endothelial injury in the microcirculation causes
endothelial cell swelling, the return of flow to base-line levels may be im-
paired, and a vicious cycle results in which low O2 delivery increases cell
volume, which increases resistance and further decreases O2 delivery.
IV. TACHYPNEA AFTER MICROEMBOLIZATION
One of the classic signs of pulmonary microembolization is the rapid

shallow breathing that can persist for several hours and that may be pre-
ceded by apnea with rapid embolization (62, 320, 539, 541). The altered re-
spiratory pattern could be due to hemodynamic or blood gas changes, such
as the arterial hypotension and hypoxemia that are the inevitable conse-
quences of microembolization. However, tachypnea occurred even when the
Pa%, the arterial partial pressure of CO2 (Pa& and the arterial pressures
are held constant after microembolization (539, 541). Because this response
does not occur after bilateral vagotomy, the tachypnea is associated with an
unidentified vagal reflex (539, 541). The mechanisms mediating the tachyp-
neic response after microembolization are not as obscure as when Whitter-
idge (539) reviewed this subject over 30 years ago. The following section
reviews this phenomenon with particular emphasis placed on the lung re-
ceptors responsible for it.
1170 ASRAR B. MALIK Vobne 63
A. Lung Irritant or Rapidly Adapting Receptors
Rapidly adapting fibers were identified by Knowlton and Larrabee (252),

who suggested that these fibers provided an excitatory input into the re-
spiratory centers and that this input balanced the inhibitory effects of slowly
adapting stretch receptors. The receptors consist of nerve endings situated
beneath the epithelial cells of larger airways (130,252,384,385), particularly
near the carina, and in the smaller bronchi (384, 441, 542). These rapidly
adapting receptors were termed irritant receptors because they are activated
by intravenous injections of irritants such as ammonia as well as by his-
tamine (348, 384, 542). The stimulation of irritant receptors induces rapid
shallow breathing that is periodically interrupted by deep breaths (62, 320,
539, 541).
The nerve endings are directly stimulated by substances such as his-
tamine, prostaglandin FZa, and serotonin (384, 541, 542), which are known
to be released during embolization (see sect. 1111). Mechanical distortion of
the nerve endings, such as with airway constriction, also causes activation
of the fibers (329, 384, 541). The increased nerve activity induced by intra-
venous injection of histamine was attenuated and sometimes abolished by
prior injections of bronchodilator agents (348); this finding suggests that the
histamine effect is not a direct one but that it occurs secondary to its bron-
choconstrictor action. It is unlikely, however, that the irritant receptors are
responsible for the sustained tachypnea associated with embolization (62,
320) because these receptors adapt rapidly (252).
B. Juxtapulwwnary Capillary Receptors (C Fibers)
Paintal (384,385) hypothesized that juxtapulmonary capillary receptors

(J receptors) mediated tachypnea when activated by the pulmonary conges-
tion produced by pulmonary microembolization. This idea stems from the
notion that J receptors are positioned to sense changes in the interstitial
fluid volume (Fig. 16); that is, the receptors are sandwiched between the
pulmonary capillary wall and the alveoli (324). The afferent fibers are slowly
conducting, unmyelinated fibers contained in the vagus and thus are easily
differentiated from the stretch receptor afferent fibers, which respond to
lung distension, and the rapidly adapting irritant receptor fibers (384, 385).
Because the slowly conducting fibers are found in other lung regions,
Paintal’s concept has been modified to distinguish between afferent vagal
fibers supplying the respiratory exchange area (i.e., pulmonary C fibers) from
those supplying the conducting airways (i.e., bronchial C fibers) (79,83,242).
The terms puhonaqy and bronchiaL therefore refer to the vascular regions
where the endings originate.
Type J receptors or C fibers do not exhibit a firing pattern associated
with normal respiration (32), but they do become activated when foreign
substances such as phenyldiguanide or capsaicin are injected intravenously
FIG. 16. Schematic representation of

type J (i.e., juxtapulmonary capillary) re-
ceptor lining interstitial tissue between
capillary and alveolus containing collagen CAPILLARY
fibrils (vertical lines). Nerve ending is stim-
ulated by increase in interstitial fluid vol- TYPE J RECEPTOR
ume or interstitial fluid pressure produced I INTERSTITIAL
during accumulation of fluid in interstitial pdg etc. VOLUME
Nervefi
space. Substances such as volatile anes- I I I
thetics or phenyldiguanide (pdg) act on re-
generative region (R) or receptor, whereas
increase in interstitial fluid volume or pres-
sure act on generator region (G) or ending.
ANAESTHETICS
[From Paintal (384).]
ALVEOLUS
(384,385). The activation of C fibers caused a reflex tachypnea in all species

studied (382,384,285); however, there were species differences. For example,
an intravenous injection of phenyldiguanide or capsaicin in cats caused ap-
nea, which was followed by rapid shallow breathing with a latency com-
patible with that of J receptors (or pulmonary C fibers) (382, 385). This
response is identical to the ventilatory response observed after pulmonary
microembolism in cats (384, 541), suggesting that the ventilatory response
to microembolism in cats may be mediated by pulmonary C fibers. Phe-
nyldiguanide had no effect in dogs (83), but capsaicin (82) produced a rapid
apnea and rapid shallow breathing similar to that observed in cats. These
species differences may reflect differences in stimulation of pulmonary C
fibers and of bronchial C fibers.
The mechanism of stimulation of C fibers after microembolization re-
mains unclear. If microembolization stimulates these slowly conducting va-
gal afferents, it is unlikely that this is to an increased interstitial fluid volume
[as Paintal (385) has suggested]-tachypnea occurs within seconds after em-
bolization when little, if any, interstitial edema would be present. In addition
no relation between pulmonary edema and the activity in slowly conducting
vagal afferents was found with alloxan-induced edema (83). Microemboli in
the small pulmonary arteries may mechanically deform the interalveolar
septa, which distorts the interstitium and may thereby stimulate the nerve
endings (169, 541). Sufficient numbers of nerve endings may not be present
in the interstitium, however, to account for the sustained tachypnea asso-
ciated with microembolization (324).
Both pulmonary and bronchial C fibers are also stimulated by the release
of humoral factors such as bradykinin, histamine, serotonin, and prosta-
glandins after microembolization (80, 83, 242). Histamine activates pulmo-
nary C fibers in rabbit (541) but not in cat (384). Intravenous histamine in
cats primarily stimulated the bronchial C fibers because latency of response
was slow and apnea rarely occurred (384). Therefore it seems reasonable to
conclude that the reflex effects of histamine on respiration in cats are due
to its entrance into the blood supply of the airways. Serotonin injected into
the pulmonary artery of cats produced a prompt apnea followed by rapid
shallow breathing (384), indicating a direct stimulation of the pulmonary
C fibers. In dogs, serotonin did not stimulate any C fibers (87,88,384). Both
bradykinin and the prostaglandins have also been shown to be potent stim-
ulators of C fibers, primarily the bronchial ones (80,242). Therefore several
humoral mediators released after microembolization are capable of activat-
ing C fibers.
A humorally mediated tachypnea is an attractive hypothesis because
substances such as histamine, serotonin, prostaglandin, and bradykinin are
released after microembolization and are known to stimulate both pulmo-
nary and bronchial C fibers (83,159,384). Stimulation of pulmonary C fibers
can occur by direct stimulation of the receptors in the alveolar-capillary
septum, whereas stimulation of bronchial C fibers occurs by transmission
of these substances via the bronchial circulation and by subsequent stimu-
lation of the C fibers contained in bronchial tissues (83).
Platelet depletion prevented the increased activity of both irritant and
C fibers after glass-bead microembolization (10). According to this evidence,
the activation of both types of fibers is due to serotonin, histamine, and
prostaglandins, which are released as a consequence of platelet aggregation.
Platelet aggregation associated with pulmonary microembolization therefore
appears to be an important component of the tachypneic response.
C Pulm~ Arterial Baroreceptors
Tachypnea during embolism can also be triggered by activating pul-

monary arterial baroreceptors (320,321). Tachypnea is associated with vas-
cular congestion upstream from the site of obstruction, which suggests that
distension of pulmonary arteries mediated the response (320, 321). A dense
network of myelinated and nonmyelineated afferent fibers terminates in the
adventitia and outer layers of the media of extrapulmonary portions of the
right and left pulmonary arteries (83-85, 456). The terminations of these
fibers were found to be most abundant at the bifurcation portion of the main
pulmonary artery. There appear to be two distinct sets of vagal afferent
fibers: 1) a set of myelinated afferent fibers in the vagus that have normal
action potentials at Ppa values of lo-50 mmHg (35, 83) and 2) a set of
receptors that are activated at very high pulmonary pressures (60-100
mmHg; 81). In addition to these vagal afferents, afferent fibers originating
from the pressure receptors in the walls of pulmonary arteries and contained
in the left cardiac sympathetic nerve discharge at Ppa values of ~40 mmHg
(364, 501).
Raising the arterial pressure of one lung after ligation of the pulmonary
veins sometimes resulted in tachypnea (84, 85). This response only occurred
with intact vagi; ventilation increased when the Ppa was increased to 80
mmHg, but the response was variable (84,85). The possibility that pulmonary
C fibers were stimulated by the pulmonary edema cannot be ruled out.
With an ingenious preparation in which a pulmonary artery pouch was
created to prevent the edemagenic effects of pulmonary hypertension and
the stimulation of J receptors, increased phrenic nerve activity and respi-
ratory rate were found to be directly related to the increased pouch pressure
(262). Vagotomy abolished these changes, suggesting a role for the pulmonary
arterial baroreceptors in the microemboli-induced tachypneic response.
However, the pulmonary arterial baroreceptors are probably not essential
in mediating tachypnea after microembolization, because the tachypnea as-
sociated with microembolization occurs at Ppa <values below 25 mmHg (4,
62,320,541); these baroreceptors are not likely to be stimulated to any extent
until rather large pressures are present in the pulmonary artery (35, 81,
364, 501).
D. Pulmonary Stretch Receptors
Pulmonary stretch receptors are thought to be located within the airway

smooth muscle (334). The primary stimulus for their activation is distension
of the lungs, and their activity persists as long as the lungs are inflated (543).
Pulmonary stretch receptors are probably not activated during pulmonary
microembolization because obstruction of pulmonary microvessels usually
causes areas of airway collapse and lung deflation (48, 350). Moreover the
primary effect of activation of stretch receptors is a slowing of the respi-
ratory rate due to an increased expiratory time (384) rather than tachypnea.
The other reflex response of stimulation of stretch receptors is bronchodi-
lation (384,385), whereas bronchoconstriction is the primary response in the
airways after microembolization (see sect. v). For these reasons, it is unlikely
that stretch receptors play a role in the tachypneic response associated with
microemboli.
E. Summary
From the above discussion it is clear that activation of any one set of
pulmonary receptors does not explain the rapid shallow breathing associated
with microembolization. Irritant receptors, C fibers, and pulmonary arterial
baroreceptors can all contribute to the tachypneic response. The irritant
receptors may be involved in initiating the response, whereas C fibers may
be involved in sustaining it. The release of mediators such as histamine,
bradykinin, serotonin, and prostaglandins after microembolization appears
to activate both receptors. Baroreceptors may also be activated after em-
bolization but only when Ppa increases to very high levels.
1174 ASRAR B. MALIK vohme 63
V. AIRWAY CONSTRICTION AFTER MICROEMBOLIZATION
A. Sites of Brmchoconstrictim
Pulmonary microembolization also causes bronchoconstriction, which

occurs primarily in the terminal airways (48,350). Histological examination
of rapidly frozen lungs after pulmonary microembolization showed constric-
tion of alveolar ducts and terminal airways (350). The diameters of the larger
airways did not change significantly (350), but because of their greater wall
thickness the larger airways may have frozen too slowly to permit assess-
ment of the degree of their constriction (73, 349). Tantalum was used after
barium sulfate microembolization to indicate a marked narrowing of airways
with diameters ~1 mm. Progressively smaller changes were seen in airways
up to 3 mm in diameter, and larger airways demonstrated no change in
diameter (73, 349). Constriction of the terminal airway was always greater
in cats than in dogs (73); these findings reflect either a greater amount of
bronchial smooth muscle or a greater reactivity of such muscle in the cat
(73, 347). The radiological evidence of constriction of small airways (73,347,
350) also agrees with the finding that the total airway resistance does not
increase significantly after microembolization (350). Constriction of the
small airways has little effect on the total airway resistance because ~80%
of the resistance normally resides in the larger airways (i.e., those >3 mm
in diameter) (285, 553).
Stein and co-workers (191,475) have challenged the conclusion that only
the peripheral airways constrict. They observed a time-dependent increase
in airway resistance, which suggested that the large airways also constricted.
A sharp decrease in the dynamic lung compliance (CL) was observed in the
first 30 s after microembolization, and this was not accompanied by a change
in airway resistance (RL). In the next 30 s, however, RL increased to levels
40% > control. The finding that CL initially decreased without any change
in RL indicates peripheral airway constriction (73, 347), but the increased
RL as CL continued to decrease also suggests central airway constriction. The
difference in findings may be related to a greater degree of embolization with
the autologous microthrombi used in Stein’s studies (191, 475), in contrast
to the degree of embolization associated with the barium sulfate microemboli
used by others (73,347,350). The platelet-fibrin microthrombi may also cause
a greater release of bronchoactive substances than barium sulfate emboli-
zation (475, 505).
The degree of embolization also appears to be an important determinant
of the airway changes (74). The CL decreased only at higher doses of barium
sulfate particles in guinea pigs, whereas the RL increased at lower doses (74),
indicating that the degree of embolization somehow determines the bron-
choconstriction site.
July 19w PULMONARY MICROEMBOLISM 1175
Selective embolization has been used to localize the site of bronchocon-

striction (191,495). Embolization of one lung with autologous microthrombi
resulted in a significant decrease in & and an increase in RL only in the
embolized lung, indicating that the effects were localized (191). The Ci, de-
creased in both lungs, however, after a unilateral. microembolization pro-
duced by injection of iodized oil into one pulmonary artery, and the change
in CL could be reversed with isoproterenol (495). This finding suggests that
peripheral airways were constricted because isoproterenol primarily dilates
the small airways (350, 495). One explanation for the contralateral bron-
choconstriction may be that the iodized oil was not confined only to the
injected lung. If the emboli were localized to the injected lung, the bilateral
constriction could also be a result of the release of bronchoconstrictor sub-
stances from the embolized lung into the blood, which then arrives at the
airway smooth muscle of the contralateral lung via the bronchial art-
eries (112).
B. Factors Aflecting Bronchoconstriction
The bronchoconstriction sites associated with emboli appear to be quite

variable from laboratory to laboratory. There are several reasons for these
differing results. Alveolar hypocapnia, which results from the reduction of
CO2 exchange in embolized lung segments, may constrict peripheral airways
(209, 450), and the arterial hypercapnia associated with embolization (108)
causes the central airways to constrict (475,477). The Pacoz and airway Pco2
have not been controlled in embolization studies; these factors may have
caused some of the variability among studies. The possibility of different
interactions occurring between various bronchoactive mediators (histamine,
serotonin, bradykinin, prostaglandins, and catecholamines) in individual
experiments may also be responsible for some of the variability. For example,
the simultaneous infusion of catecholamines can reverse the constrictor ef-
fect of histamine or bradykinin on bronchioles (352; 399); therefore the typ-
ical bronchoconstrictor response induced by microembolization would be
markedly attenuated if the dilating substances are released by the emboli
to a greater extent than are the constricting substances. In addition the
degree and site of airway constriction depend on the prevailing smooth mus-
cle tone in the airways (516), and the use of anesthetics and muscle relaxants
may reduce bronchial smooth muscle tone (540). There was a smaller increase
in RL after embolization if large airways were previously constricted because
of either increased vagal tone (173) or decreased lung volume (516). Therefore
RL would presumably increase more if larger airways were dilated before
the embolization occurred. Finally, differences in the degree of embolization
and in the methods of producing it (which result in different concentrations
of bronchoconstrictor agents) may also explain the lack of agreement.
C. Mechanisms Involved in Producing Bronchoconstriction
The existing physiological evidence indicates that primarily the small

airways constrict and that this is mediated by humoral mechanisms. The
evidence supporting the constriction of large airways is equivocal; when large
.airway constriction does occur, however, it is mediated by neural mecha-
nisms.
1. Humoral mechanisms
The constriction of small airways appears to be chiefly mediated through

humoral factors, because the decreased CL associated with emboli can be
inhibited by antagonists of serotonin, histamine, and prostaglandins (‘78,191,
350). Also, 2 min are required for small airways to become maximally con-
stricted after embolization (350, 475, 476), whereas vagally mediated con-
striction occurs in seconds (73,347,350). In addition the constriction of small
airways after barium sulfate embolization cannot be blocked by atropine or
vagotomy (350). Finally, powerful bronchoconstrictor agents such as hista-
mine, bradykinin, serotonin, and prostaglandins are known to be released
from aggregated platelets and leukocytes in plasma and by mast cells after
microembolization (363, 432).
Vaage and co-workers (509, 511, 512) have assessed the relative contri-
butions of each humoral factor to bronchial constriction. A temporal rela-
tionship was established between the increased airway pressure in the cat
after collagen-induced embolization and the contraction of in vitro smooth
muscle bioassay preparations superfused with pulmonary venous blood from
the same animal. The smooth muscle samples were pretreated with antag-
onists of catecholamines, histamine, serotonin, and acetylcholine (330, 509,
511, 512), which eliminated these compounds as bronchoconstrictive agents.
Prostaglandin-like activity was demonstrated with this bioassay system, and
indomethacin inhibited the contraction of smooth muscle (511). Clay and
Hughes (14) also inhibited the embolization-induced increase in airway re-
sistance with indomethacin in intact guinea pigs. Therefore prostaglandins
significantly mediate the bronchoconstriction associated with embolization.
The humoral factors responsible for constriction of small airways are
released as a consequence of intravascular coagulation or platelet aggre-
gation (437, 492, 507), because airway changes are inhibited or at least at-
tenuated by either platelet depletion (41,403,505,507,509) or heparin (267).
If this is the case, the number of mediators released should be reduced in
thrombocytopenic animals. Radegran (403, 404) demonstrated this effect in
a cat preparation.
Once formed, the mediators probably diffuse from the blood vessels into
the lung interstitium and then to the smooth muscle of small adjacent air-
ways. This method of mediator dispersion is supported by the finding that
constriction of the larger airways after microembolization (when it occurs)
is delayed and is much smaller in magnitude when compared with the re-
sponse of small airways (475, 476).
2. Neural factors
When microembolization produces increased RL (191,475,476), it occurs

rapidly, suggesting a reflex arc. Sectioning of the cervical vagi or adminis-
tration of atropine partially or completely reduced the change in RL (191).
The decreased CL was unaffected by these maneuvers (191, 403, 505). Vagal
stimulation caused constriction of airways 3-8 mm in diameter in dogs (160,
191, 476, 505, 553).
a) Irritant receptors. The reflex may be mediated by histamine acting
on the irritant receptors in the mucosa of large airways (385,543). The reflex
elicited by stimulation of these receptors can be blocked by atropine and by
cooling or cutting the vagi (112), but the effects of antihistamine are
not known.
A 118% increase in RL and a 14% decrease in & occur within 14-18 s
after injection of histamine directly into bronchial arteries in dogs (112).
The degree of reflex activation may therefore depend on the concentration
of histamine after embolization; the failure to observe an unequivocal con-
striction of large airways may reflect the degree of embolization and the
amount of histamine released (138, 432).
The irritant or rapidly adapting receptors responsible for the reflex
phenomena just described are situated beneath the epithelial layer of the
trachea, and the major airways are supplied by myelinated vagal fibers (385,
543). They are chemical-type receptors stimulated by substances (such as
histamine) that are liberated by microembolization (83,384,385). In addition,
they are also mechanically stimulated by alterations in lung volume, con-
traction of adjacent smooth muscle, and pulmonary congestion (384, 385),
changes that also occur as a consequence of microembolization. These re-
ceptors may respond differently in different species in terms of the magnitude
(21,73,239), but it is not certain that the lungs were embolized to the same
extent in all studies.
Another property of irritant receptors is that their stimulation has very
diffuse effects. Stimulation of receptors in the lower airways with histamine
causes constriction to occur in the upper airways (351, 353), whereas me-
chanical irritation of upper airway receptors constricts lower airways (160).
Furthermore, a stimulus localized to one lung causes constriction within the
other lung (112). These widespread effects may explain the constriction seen
in both lungs after microembolization of one,lung (495).
b) Juxtapulmonary capdlary receptors. Paintal (383-385) believes that
the bronchoconstriction that follows microembolization is due to stimulation
of the J receptors (i.e., pulmonary C fibers). Furthermore, because these
receptors are found in the alveolar septal space, it is hypothesized that em-
bolization of small pulmonary arteries stimulates them by distorting the
1178 ASRAR B. MALIK Vohrne 63
alveolar septa (324). The role of pulmonary C fibers in producing broncho-

constriction associated with microembolization is uncertain, however; bron-
choconstriction can be produced by simply occluding a large pulmonary ar-
tery with a balloon when there is not likely to be a marked distortion of the
alveolar septum (451). Stimulation of the J receptors via histamine, pros-
taglandins, and other mediators released after embolism may be a more
likely mechanism of their activation.
3. Airway hypocapnia
Some changes associated with pulmonary microembolization may be

related to decreases in the partial pressure of CO2 (Pco~) of lung units not
receiving CO2 from mixed venous blood. Ingram (209) showed that a de-
creased alveolar Pco2 produces a large decrease in static lung compliance
and only a small increase in R L, a response similar to microembolization.
Severinghaus et al. (451) demonstrated that the bronchoconstriction asso-
ciated with occlusion of a pulmonary artery was prevented by adding an 8%
mixture of C02. Because the tone of the small airways was unchanged in
the normal lung after breathing this mixture, the effect of CO2 in preventing
the bronchoconstriction was only the reversal of alveolar hypocapnia (164,
352). Alveolar hypocapnia may therefore be an important factor in producing
bronchoconstriction after microembolization only when portions of the’ cir-
culation have been totally blocked by the procedure (145, 228, 259, 495).
D. Homeostatic Value of Brmchoconstriction
Studies have demonstrated that airflow to an embolized lung decreases

within a few breaths, whereas airflow to the unobstructed lung increases
(247, 451, 515). This tends to maintain a near-normal VA/(). In addition,
hypoxemia is greater when bronchoconstriction is prevented by ventilating
with a C02-rich gas mixture at the time of embolization (451,482). Thus the
bronchoconstriction associated with pulmonary vascular obstruction is a
homeostatic mechanism similar to the pulmonary vasoconstriction that oc-
curs with hypoxia. Both mechanisms serve to improve the VA/Q inequality
that would otherwise result.
The redistribution of airflow from the embolized lung occurs in two
stages (266) resulting from two distinct mechanisms. There appears to be
an initial nonuniform bronchoconstriction caused by humoral and neural
mechanisms followed by a bronchoconstriction in the embolized lung regions
related to the airway hypocapnia. The initial airflow shift from the ob-
structed lung units is followed by an even greater shift. During the initial
stage, the airflow shift has been related to the release of various broncho-
constrictor substances that cause diffuse constriction in nonembolized and
embolized segments. Therefore the redistribution away from embolized re-
gions was not as marked as would have been expected had the constriction
July 1983 PULMONARY MICROEMBOIJSM 1179
been confined solely to the embolized regions (266, 491, 492). The diffuse
bronchoconstriction is due to the release of humoral factors (which are as-
sociated with intravascular coagulation), because heparin resulted in a more
uniform constriction that was confined to the embolized regions (266). The
second stage of the airflow response, in which bronchoconstriction is localized
to the embolized lung units, is mediated by airway hypocapnia, because it
could be prevented by adding CO2 to the inspirate (266).
E. Alveolar Dead Space After Embolixation
Alveolar dead space either increases (134, 301) or remains unchanged

after pulmonary embolization (108). The variability of the response reflects
the degree of redistribution in airflow associated with the emboli. If the
ventilation distribution remains unchanged, alveolar dead space increases
by an amount equal to the original VA of the occluded lung segment; but if
total ventilation of the occluded lung is diverted into the perfused lung, the
dead space increases by the lung volume of the unperfused lung. Because
ventilation is only partly redistributed from embolized lung units (108) and
because .the degree of redistribution is a time-dependent phenomenon (451),
any measured change in dead space after pulmonary embolism reflects the
amount of airflow redistribution. Therefore the measurement of dead space
is not a reliable index of the degree of vascular obstruction (450). Another
complicating factor is that emboli producing incomplete vascular obstruction
result in a lower dead-space value than emboli producing total obstruction
(134), presumably because the incomplete obstruction allows some perfusion
to continue to the lung segments.
F. Alveolar Collapse
Collapse of alveoli is usually observed with pulmonary microemboliza-

tion (48,350). The blockage of terminal airways by bronchoconstriction may
explain segmental atelectasis occurring within 1 h after embolism (350). The
alveoli collapse as a result of the airway closure because the gases trapped
in the alveoli diffuse down concentration gradients into the blood. The most
common site of alveolar collapse is in the dependent lung (350), because the
lung parenchyma is less expanded; thus microembolism-induced broncho-
constriction can more easily produce airway closure.
Atelectasis can also be related to the loss of surfactant activity asso-
ciated with pulmonary vascular obstruction (69). Finley et al. (131) found
that fluid extracts from lungs whose arteries had been ligated for 12-16 h
had high surface tensions. Giammona et al. (153) observed an increased
tension as early as 4 h after ligation of a pulmonary artery. Morphological
and biochemical studies indicated that alterations in phospholipid and di-
palmityl phosphatidylcholine levels occurred only within atelectatic areas
1180 ASRAR B. MALIK l%hme 63
of the occluded lung (122,200,339). The studies of Finley et al. (131), however,
demonstrated a more generalized type of alteration in surfactant activity,
severe congestion, and atelectasis after occlusion of a pulmonary artery. The
different findings may represent varying degrees of collateral bronchial blood
flow (528,547). Although the severity of the lesions was variable, both studies
indicated that lung vascular obstruction somehow interferes with surfactant
metabolism and that it results in alveolar instability. These changes in al-
tered surfactant metabolism ‘are not easily reversed: the obstructed lung
differed from a contralateral lung in having a smaller fraction of total air
volume returned at each transpulmonary pressure during deflation, even
after 2 wk (153).
The mechanisms responsible for surfactant inactivation are unknown.
Perhaps the leakage of plasma proteins into the alveolar spaces (388) some-
how inactivates surfactant (222). Although pulmonary embolism is known
to cause an increased microvascular permeability, its effect on the epithelium
may be less severe unless the embolism is severe (92,131,153,303). It is also
possible that a direct ischemic injury to the metabolically active surfactant-
producing type II alveolar epithelial cells could result from decreased pul-
monary and bronchial perfusion of the obstructed segments (72, 302, 303).
The return, of surface activity toward normal values several weeks after
embolization also parallels the development of nutrient collateral circula-
tions (153, 200, 339).
The hypothesis that pulmonary ischemia could deplete surfactant has
been supported by the observation that pulmonary arterial occlusion reduces
the density of lamellar bodies in type II alveolar epithelial cells by 80%;
these bodies are the intracellular storage sites for surface-active phospho-
lipids (26, 454). Reperfusion for 6 h was not sufficient to reestablish normal
type II cell morphology (26, 454).
VI. MECHANISMS OF ARTERIAL HYPOXIA
Rapid development of hypoxemia is a major consequence of pulmonary

embolization (420). Hypoxemia is not caused by pulmonary edema-the
Paoz decreases immediately after pulmonary microembolization (301), and
no substantial accumulation of edema fluid occurs during this time. The
hypoxemia is caused by right-to-left shunting (&,/&,; 245), alveolar-capillary
impairment of O2 diffusion (58, 226, 455), regional TjA/t$ inequalities (108,
267, 268), and alveolar hypoventilation (108, .420). The relative contribution
of each of these factors is discussed in the following section.
A. Time Course of Gas-Exchange Impakvnent
A decrease in Paoz occurs within minutes after pulmonary microem-

bolization induced by emboli of varying sizes and compositions (301). In
experiments in which blood clots were used to produce microembolization,

hypoxemia was associated with alterations in the distributions of VA and
&, which caused a VA/Q mismatch (108). The VA/Q inequality after embo-
lization with thrombi was transient, however, because recovery began 15
min after embolization and was complete after 2 h (108). Restoration of the
normal VA/Q was probably caused by dissolution of the blood clot, resulting
in a gradual return of blood flow and ventilation to normal values (101,417).
The Paoz decreased immediately after embolization with glass beads;
nevertheless, in contrast to the effect of embolization with blood clots,
Pa% continued to decrease steadily (301). The latter decrease in Pao, in these
experiments was associated with interstitial edema and, in some cases, with
alveolar flooding (301). This steady decline in Paoz did not occur when pul-
monary edema was prevented by prior treatment with heparin (301).
B. fi$‘jFu.sion Impairment
Because Paoz decreases immediately after microembolization when there

is no evidence of alveolar flooding, a diffusion impairment across the alveolar-
capillary membranes cannot explain the observed hypoxemia. Moreover the
small decreases in diffusion capacity of carbon monoxide (2533%) that have
been observed after microembolization (58, 267) indicate no appreciable al-
veolar-capillary barrier to O2 diffusion (226,455). Other emboli studies have
shown no change in the diffusion capacity of carbon monoxide but a consid-
erable degree of hypoxemia (245); therefore a diffusion impairment can be
ruled out as being primarily responsible for the hypoxemia associated with
microembolization. This does not preclude the increase in alveolar-arterial
PO, gradient that may occur after marked pulmonary arterial obstruction
due to an increased blood velocity through the remaining lung segment and
the resulting decreased transit time.
C. Iweased Venous Admixture
1. Acute increase
A rapid increase in the Qs/@ of blood through the lungs could be caused
either by the opening of arteriovenous communications or by an increased
percentage of blood flow occurring through collapsed lung units. Such an
increase could explain the rapid development of hypoxemia. But @/Qt does
not change in a predictable fashion (266,267); in fact Qs/@ sometimes does
not change at all, despite the presence of hypoxemia (108). These differences
could be explained if the embolization caused airway closure or constriction
and alveolar collapse. Caldini (63) reversed the increase Qs/Qt after em-
bolization in dogs by applying positive end-expiratory pressure and reex-
panding the alveoli. Moreover an increased venous admixture was not ob-
served after glass-bead microembolization in dogs pretreated with heparin

(267,.301), suggesting that inhibition of intravascular clotting prevents air-
way constriction and the resulting alveolar collapse.
A sudden increase in pulmonary arteriovenous shunting produced either
by an increased collateral bronchial blood flow (15, 56) or by an opening of
parallel pulmonary arteriovenous shunts (135, 136) may be another expla-
nation for the rapid increase in @/Qt. The bronchial blood flow, however,
does not increase immediately after embolization (299), and therefore an
increased collateral bronchial blood flow is probably not a cause of the in-
creased shunting. The opening of parallel pulmonary arteriovenous pathways
is also not likely because no evidence indicates their existence in normal or
embolized lungs (108,135,136,296). Another latent (but unproven) cause of
an acvte intx!wksst& C&$$Ld~kkhR a yi&wxCtiy y3hn!t G3mmsec wake tkat
may open if the right atria1 pressure exceeds the left atria1 pressure after
pulmonary vascular obstruction.
2. Delayed increase
In addition to the acute change, Qs/@ also increased slowly after em-
bolization (549). The delayed increase observed 19 days after an embolic
episode could be reversed by deep breathing, indicating alveolar collapse
(549). This increase may be related to alveolar collapse from loss of surface-
active material (549) as a consequence of prolonged pulmonary hypoperfusion
and impaired surfactant production (72, 498, 528). Possibly the fibrinolysis
occurring after embolization clears emboli before the surface-active prop-
erties are restored (101); therefore Qs/Qt would increase because the vessels
are perfused, but the alveoli would not exchange gas.
The increased collateral bronchial blood flow, which occurs over a period
of days after embolization (15), may also be responsible for the delayed &s/
&t increase. Bronchopulmonary collateral blood flow shunts venous blood
into the pulmonary circuit (15). Collateral blood flow increases markedly
over a period of months (528), and a two to threefold flow increase has been
observed as early as 2 wk (245). Because the O2 saturation of the broncho-
pulmonary effluent blood averages only 50% (15), any increase in the bron-
chopulmonary flow would result in an increase in @/Qt.
D. Ventilation-Perfusion Imbalance
The most important cause of arterial hypoxemia occurring immediately

after pulmonary microembolization is an imbalance in regional ventilation
and perfusion. This VA/Q imbalance is caused by embolization of pulmonary
arteries, because embolization alters the distribution of pulmonary perfusion
(265, 301, 302). This redistribution of & produces regions havinglow VA/Q
values (log), which is the primary defect responsible for the hypoxemia
associated with microembolization (133, 283, 349).
A two-compartment lung model (described in Fig. 17) has been used to

explain the VA/Q imbalance (108). In this example, one compartment ini-
tially receives 83% less of the ventilation and blood flow and the other re-
ceives 17% of each. If the pulmonary artery of the smaller segment is em-
bolized so that 90% of its base-line blood flow is diverted, the VA/t& of the
smaller segment would be increased to 10, whereas the VA/Q of the larger
segment would only decrease from 1.0 to 0.9. But if the larger segment is
embolized and only 50% of its base-line flow is diverted to the other lung,
the VA/t) of the smaller segment would decrease from 1.0 to 0.3, whereas
the VA/Q of the larger segment would increase to 2.0. Thus in the second
case there is a region of the lung with a VA/Q value <l, and as a result the
hypoxemia is more severe. In addition the degree of hypoxemia is more
severe after the embolization of the larger segment and a shifting of blood
to a region with low ventilation (108,266). The difficulty with this particular
model is that only the redistribution of blood flow occurs and the ventilation
to the embolized lung segments remains unchanged. This assumption is in-
valid because airflow is diverted away from embolized to nonembolized lung
units (266, 451). The airflow redistribution would serve to minimize the de-
crease in &A/Q, and hence the severity of hypoxemia would be less than
predicted from the example shown in Figure 17.
Alterations in VA/Q appear to develop only when vessels larger than
150 pm in diameter are embolized. Injections of beads larger than 150 pm
in diameter always produced regions with low VA/Q, but smaller emboli did
not have the same effect (556). Small emboli do not cause a significant VA/
& imbalance: the numerous capillary interconnections continue to allow per-
fusion of the lung tissue distal to obstruction (248), whereas perfusion is
shunted to nonembolized regions with the larger emboli.
I. Huwwral mechanism of ventilation-perfusion imbalance
Platelet aggregation plays a major role in mediating the VA/Q irreg-

ularities associated with microembolization. The development of hypoxemia
after ADP-induced platelet aggregation was comparable in both time course
and severity to the hypoxemia associated with microembolization (333). The
hypoxemia was prevented by platelet depletion before the ADP injection
(333); therefore platelet aggregation occurring after pulmonary microem-
bolization and the concomitant vasoactive and bronchoactive substances re-
leased from activated platelets are primary factors in producing the VA/Q
imbalance (506, 534).
E. Alveolar Hgpventdation
Sudden embolization is commonly associated with a period of rapid shal-

low breathing (48, 320, 539, 541). Although minute ventilation may be in-
creased (62, 320, 41?), the rapid shallow breathing could produce alveolar
SMALL LARGE
COMPARTMENT COM~%RTMENT
HOMOGENEOUS LUNG
PRE-EMBOLIZATtON
ARTERIAL PO, 104
ARTERIAL Pco, 39
SMALL COMPARTMENT
EMBOLIZED
ARTERIAL PO, 98
142 98
pop ARTERIAL PC02 40
I6 40
pco,
.
v* 1.0
LARGE COMPARTMENT
0 3.5
EMBOLIZED
it*/6 0.3
ARTERIAL Po2 66
PO2 58 ARTERIAL PC02 40
pco, 44
FIG. 1’7. Two-compartment lung model with pulmonary blood flow (&) and alveolar ven-
tilation (VA) in liters/min. Both VA and & are matched in top pan@ & to smaller compartment
is reduced by 90% in middle pan& and & to larger compartment is reduced by 50% in bottom
panel. Changes in VA, &, VA/Q, and POT and PCop of blood from each compartment (Zefi) are
indicated along with mired arterial partial pressure of O2 (POT) and partial pressure of CO2
(PC@) values (right). [From Dantzker et al. (lOS).]
hypoventilation and arterial hypoxemia (326). Because hypoxemia also oc-

curred after embolization in conditions of controlled ventilation (301), al-
veolar hypoventilation probably is not responsible for the observed arterial
hypoxemia. Alveolar hypoventilation occurs in spontaneously breathing an-

imals after embolization (log), however, and in these instances it may con-
tribute to hypoxemia.
VII. BRONCHIAL BLOOD FLOW
Morphological studies indicate that the bronchial arteries in most mam-

mals supply the bronchial tree, including the terminal bronchioles and pul-
monary vasa vasorum (104, 328). The pulmonary arteries supply the small
respiratory bronchioles, alveolar ducts, and alveoli (316, 317). Injection of
histamine into the pulmonary artery results in constriction of the alveolar
ducts only, whereas injection into a bronchial artery causes constriction of
the larger airways (112). Von Luschka (520) referred to the bronchial arteries
as the “vasa privata” to distinguish them from the pulmonary arteries, the
“vasa publica.”
A century ago Virchow and Gesammelte (517) demonstrated that pul-
monary infarction rarely occurred after ligation of a main pulmonary artery.
An increased amount of collateral bronchial blood flow entering embolized
portions of the lung prevents necrosis, but the mechanism of this protective
effect is not well understood. Bronchial blood flow normally represents only
l-3% of the cardiac output (104), and it is markedly increased after em-
bolization (124,299,517,528). Although there is good evidence that bronchial
blood flow is increased (275, 389, 547), the rapidity with which the flow in-
creases after vascular obstruction and the factors that mediate the increase
are not yet well understood. The following section contains a review of the
normal pattern of bronchial perfusion, the factors that regulate the bronchial
blood flow, and the extent to which these factors participate in bronchovas-
cular regulation after pulmonary embolization.
A. Anatomy and Physiology of Bronchial Circulation
1. Pattern of normal bronchial perfikm
There is much interspecies variability in the origin and distribution of

the bronchial circulation (104, 316, 317, 366). The most thoroughly studied
system has been that of the dog (56,104,366), and as seen in Figure 18, the
pattern in this animal is quite complex. Some generalizations can be made.
1) In all mammals the bronchial artery forms a capillary bed (Fig. 18), which
primarily drains the airways to the level of the terminal bronchioles (104).
2) The bronchial capillary bed drains into the bronchial veins, which then
return the blood to the right atrium either directly or via the superior azygos
vein (Fig. 18); the alternate pathway is through the bronchopulmonary anast-
omoses, which drain blood directly into the precapillary and postcapillary
pulmonary microvessels (Fig. 18; 104, 316, 317, 366).
6 VISCERAL PLEURAL BED
0 n 1
PULMONARY ARTERY
5 PULMONARY
0 VASAE VASORUM '-\
BRONCHIOLAR BED
4 BRONCHIAL BED
u
BRONCHIAL VEIN
SUPERIOR VENA CAVA PULMONARY VEIN
RIGHT BRONCHIAL ARTERY
O--A-
AORTA
FIG. 18. Vascular connections of right posterior bronchial artery in dog. Heaw line indicates arteries. Components of bronchial circulation
are: 1) alveolar-capillary bed of pulmonary circulation; 2) capillary bed of respiratory bronchioles showing anastomoses with alveolar vessels that
are supplied by pulmonary artery; 8) capillary bed supplying lung parenchymal tissue; 4) bronchial capillary bed supplying. larger airways that
drain into true bronchial veins and in turn drain into azygos vein and superior vena cava; 5) pulmonary vasa vasorium, i.e., nutritional vessels of
pulmonary vessels; and 6) visceral pleural capillary bed supplied by both pulmonary arterial system and bronchial arterial system. [Adapted from
Bruner and Schmidt (56).]
The percentage of total bronchial arterial flow that enters pulmonary

vessels relative to that draining into the bronchial veins is highly variable.
Apparently 30-70s of the total bronchial arterial inflow passes through the
bronchial veins, and the remaining flow drains into the pulmonary vessels
via the anastomoses (7, 8). However, the techniques used to measure the
anastomotic flow are crude, and the flow values are not known quantitatively
(547, 558).
Although anastomoses have been demonstrated in rat and guinea pig
lung (316,317), they do not seem to be well developed in dog, cat, and primate
lungs (316, 317). [In fact, they are nonexistent in rabbit lungs (317).] Their
function has not yet been documented, but the prominence of anastomoses
in some species may be related to greater requirements of nonrespiratory
tissue for oxygenated blood.
2. N-1 bronchial bloud&w values
Attempts have been made to quantify bronchial blood flow, but in most
instances extensive surgery is required to conduct the measurements (366).
In addition the bronchial blood flow appears to vary spontaneously in a
wavelike fashion, having a period of ~2 min (56). The basis for this phe-
nomenon is not clear, but it may be caused by bronchial spasms associated
with the extensive surgery.
As measured with a bubble flowmeter in dogs, the bronchial arterial
blood flow in the right posterior bronchial artery averaged 4.8 ml/min (56).
This measurement did not include flow to the left lung or contributions to
the right lung made by minor bronchial arteries. Total bronchial blood flow
was estimated to* be 1% of the cardiac output (56, 104). Table 3 provides
measurements of bronchial blood flow in dogs. These measurements were
obtained by using labeled microspheres 15 pm in diameter. Bronchial blood
flow represents Z-3% of cardiac output in these studies (299), which probably
reflects a more realistic estimate of bronchial blood flow. The microsphere
TABLE 3. Bronchial blood flow afier ernbolizatim

Bronchial Blood Bronchial Blood Airway Blood Flow,
Bronchial Blood Flow, ml min-’
l l Flow, 5%~of ml min-’
l l 100 g
Flow, ml/min 100 g dry lung-’ Cardiac Output dry wt-’
Group I
Base line 31.2 AI 6.2 83.4 k 23.1 1.6 k 0.5 33.6 t 6.8
5 min PE 42.5 t 9.5 111.2 k 32.3 1.9 t 0.8 46.0 k 15.3
60 min PE 8.6 AI 2.2* 23.5 t 4.2” 0.7 t 0.2” 35.7 k 8.4
Group II
2wkPE 178.9 t 7’7.6’ 359.2 t 145.1*-t 7.0 t 2.8*? 50.8 t 16.3
Values are means t SE. PE, postembolization times. * Different from base line (P
< 0.05). t Different from 5 and 60 min PE (P < 0.05). [From Malik and Tracy (299).]
technique requires relatively little surgery, but it is necessary to correct for

the number of tissue microspheres that shunt through peripheral arterio-
venous anastomoses, and the correction factor is substantial (50-100%). The
total bronchial arterial blood flow has also been estimated by creating a
pouch in the portion of the descending aorta from which the bronchial ar-
teries orginate (198). All arteries originating from the aorta except the bron-
chial arteries are ligated, and blood flow in the ascending aorta is shunted
to the descending aorta. The flow of blood through this pouch was then
measured with a rotameter. In dogs with intact nervous systems the bron-
chial arterial flow averaged 30 ml/min, which is similar to the microsphere
estimates (198).
Another technique for estimating bronchial flows involves ligating the
pulmonary artery and vein in the left diaphragmatic lobe and sampling the
blood flow coming through an outflow cannula placed proximally to the ve-
nous ligation (8, 15, 547). The flow represents the bronchopulmonary anas-
tomotic flow because no pulmonary blood flow exists. The mean value for the
bronchopulmonary flow in the left diaphragmatic lobe ranged from 3.8 to
6.5 ml/min (15, 547). Because the lobe represents 26.2% of lung weight, the
total bronchopulmonary flow reaching the left atrium was estimated to be
18.3 ml/min. The flow may not represent true anastomotic flow, however,
because ligation of the pulmonary artery may in itself alter the flow dis-
tribution.
The bronchoesophageal artery in the intact sheep has also been used to
measure bronchial blood flow, because it is believed to be the major source
of bronchial blood flow in sheep (287). Estimates of flow measured with
electron magnetic flow probes ranged from 5 to 14 ml/h, or only 0.4% of the
cardiac output (287). These estimates suggest that there is a low bronchial
blood flow in sheep or that other arteries supply much of the bronchial blood
flow. Bronchial blood flow has been estimated in sheep with the aortic-pouch
technique (558), and valueslare twice as high as those reported in the bron-
choesophageal artery (287).
Some generalizations can be made about the normal bronchial blood
flow. 1) The flow is an extremely small portion of total cardiac output (rep-
resenting only l-3%), but in absolute units the flow is 30 ml/min. 2) The
microsphere method is less traumatic and is the most physiological method
for measuring bronchial blood flow. 3) The relationship between the relative
fractions of bronchial blood flow entering the true bronchial veins and the
fractions entering the anastomoses needs further quantification.
B. Eflects of Pulmonary lkficnwnbolization on Bronchial Bloud Fbw
I. Acute alterations
Branch i al blood flow measured in dogs with labeled microspheres in-

jetted into the left atrium indicates th at flow did not decrease from base-
line levels at 5 min after glass-bead microembolization but was decreased

at 60 min (see Table 3). Moreover the decreased flow was associated with an
increased bronchovascular resistance (299), implying vasoconstriction at
some vascular element within the bronchial circulation. The time lag prob-
ably indicates some systemic vasoconstrictor agents being slowly released
after microembolization rather than some rapidly acting neural mecha-
nisms (88).
2. Consequences of bronchial hypoperfidm
The decreased bronchial blood flow observed after microembolization

is of pathological significance because normal bronchial perfusion is nec-
essary to maintain the tissue integrity of the lung (389, 517). Alterations in
morphology, surface-tension properties, and regional ventilation occurred
as early as one day after ligation of a pulmonary artery (389), presumably
because collateral bronchial perfusion cannot maintain adequate oxygena-
tion and substrate delivery to the bronchial structures.
In the dog, the minimal blood flow requirement was estimated to be 5
ml min-l *kg-l body wt, which is -5% of cardiac output (87, 498). When
l
pulmonary blood flow is stopped after microembolization, the flow require-

ments must be met by an increased bronchial blood flow; however, because
bronchial blood flow was reduced to one-third of the base-line value within
60 min after embolization, this system may not provide adequate O2 and
substrates to the alveolar structures and small airways (299). The cells likely
to be affected by poor oxygenation and substrate delivery are the metabol-
ically active cells, such as the type II alveolar epithelial cells that synthesize
surfactant and the endothelial cells that modify several vasoactive factors
(see Table 2; 138).
3. Regulation of bronchial blood jlow
This section discusses the. neurohumoral and mechanical factors in-

volved in the regulation of bronchial blood flow and how these factors con-
tribute to the observed decrease in bronchial blood flow after microembo-
lization (299).
a) N&urohuwwraZ factors. The bronchial circulation is under greater
neurogenic and humoral control than the pulmonary circulation (104, 129).
Sympathetic stimulation results in bronchial vasoconstriction, and vagal
stimulation results in vasodilation; these effects can be inhibited by appro-
priate antagonists (56). The bronchial circulation also demonstrates tonic
neural control, because flow increases after sectioning of the sympathetic
nerves and decreases after sectioning of the vagus (56). Epinephrine and
norepinephrine cause vasoconstriction and decrease the bronchial blood flow
(56). Serotonin and histamine, which are released after pulmonary microem-
bolization, are bronchial vasodilators (299). Sympathetic factors may there-
1190 ASRAR B.MALIK Vdume 63
fore contribute to the postembolization bronchial hypoperfusion, because

sympathetic stimulation is one of the few interventions that clearly produces
bronchial vasoconstriction (56).
Sympathetic nerve stimulation and catecholamine infusions decreased
bronchial arterial flow and bronchial venous outflow, but the bronchopul-
monary anastomotic flow increased (56,310). These studies suggest that the
primary sites of constriction associated with sympathetic stimulation (and
by inference with microembolization) are the bronchial veins (104).
Hypoxemia and hypercapnia of the bronchial artery blood flow have also
been shown to cause increased bronchial vascular resistance (56, 283, 299).
However, breathing a gas low in O2 (7.5 or 10%) and high in CO2 (5 or 7%)
appears to cause vasodilation and increased bronchial blood flow (56). Thus
the responses to hypoxemia and hypercarbia in the bronchial circulation are
not clear at this time, nor is it clear to what extent the’changes in blood
gases influence bronchomotor tone after microembolization.
b) lMechanicaZjii&xw. I) PERFUSIONPRESSURE. In addition to the neural
and humoral factors already discussed, a decrease in bronchial perfusion
pressure can also produce bronchial hypoperfusion (12440,531). In a prep-
aration in which the pulmonary and bronchial vascular beds were separately
perfused so’that the systemic arterial pressures or the Ppa values could be
independently varied, the bronchial blood flow decreased as the systemic
artery-pulmonary artery pressure gradient was decreased, and the flow in-
creased as the gradient was increased (12, 440, 531). Thus bronchial blood
flow is dependent on the perfusion pressure and does not appear to auto-
regulate when pressure is altered. Aramendia et al. (7), however, have dem-
onstrated that flow in true bronchial veins (i.e., the veins draining the bron-
chial blood flow into the right atrium) was constant in half of the animals
at perfusion pressure >lOO mmHg, yet total bronchial blood flow did not
remain constant. Therefore a portion of the bronchial circulation (bronchial
veins) may regulate its blood flows by other means (i.e., by humoral mech-
anisms such as adenosine). The decreased bronchial blood flow associated
with embolization may be explained by the perfusion pressure because the
systemic arterial-pulmonary arterial pressure gradient was decreased (299).
II) SYSTEMIC VENOUS HYPERTENSION. Systemic venous hypertension,
which is associated with severe pulmonary microembolization (438), can also
reduce bronchial venous flow and can thus contribute to the decreased bron-
chial blood flow observed after microembolization (56). Nevertheless the au-
toregulation of the bronchial veins may prevent significant changes in bron-
chial venous pressure resulting from systemic venous hypertension (7).
A Long-term alterations
One year after pulmonary ar ltery ligation, the collateral blood flow in
the left lower lobe had increased dramatically from the base-line range of
4-9 ml/min to 38-39 ml/min. The value of the compensatory enlargement

of the bronchial arteries is obvious because infarcts were never seen in the
obstructed vessels (122, 125, 183, 200, 274), although necrosis and infarcts
were common when collateral flow was not allowed to increase by chronically
reducing the systemic arterial pressure (389).
In addition to maintaining substrate-delivery and preventing tissue in-
jury, another important consequence of increased bronchial circulation is
that it allows gas exchange to occur to some extent in the obstructed lung
segments (276). Three years after ligation of the left pulmonary artery in
dogs there was only a slight decrease in ventilation of the left lung (from
the preligation value of 42.5% of the total ventilation to 34.5%), and O2
uptake in the left lung was reduced to only 11% of the total (276). The
increased bronchial circulation after chronic pulmonary arterial obstruction
allowed O2 uptake to continue, although at a reduced rate.
Weibel(528) has made a quantitative assessment of the long-term bron-
chial vascular alterations after pulmonary vascular occlusion. Proliferative
changes in the endothelium and media of bronchial arteries were observed
5 days after ligation of a pulmonary artery. These changes were accompanied
by the formation of new bronchial arteries as well as by enlargement of
preexisting vessels. An increase in bronchial blood flow was also noted with
the microsphere technique after glass-bead microembolization (299); the flow
increased from 2% of cardiac output to 7% of the cardiac output within a
relatively short period of 2 wk (Table 3). Chronic hypoxemia cannot be im-
plicated as the mechanism of the increased vascularity, because bronchial
blood flow did not increase in sheep born and raised under hypoxic conditions
at high altitude (558). Because new vessels were found in both ligated and
nonligated regions of the lung, Weibel’s (528) suggestion that vessel prolif-
eration after pulmonary artery obstruction occurs as a result of release of
“antiogentic factor(s)” is a reasonable one.
VII. CONCLUSIONS
Recent studies have reaffirmed the view of Starling and Verney (469)
that the pulmonary circulation serves as a filter for the removal of humoral
substances such as serotonin and also for the removal of particulate matter
originating in the peripheral circulation. Owing to this filtering function
there are certain homeostatic adjustments (such as the bronchoconstriction
and vasoconstriction occurring primarily in areas in which vessels are ob-
structed) that tend to minimize the deleterious effects of vascular obstruc-
tion. Bronchoconstriction and vasoconstriction lessen the ventilation and
perfusion imbalance that would otherwise occur. Enlargement of the bron-
chial circulation is an example of a long-term alteration that occurs after
pulmonary vascular obstruction. The anatomical and physiological change
minimizes necrosis within pulmonary tissue and allows for some gas ex-
change to occur even though pulmonary arteries are obstructed. The ability
of the lung to receive particulate matter from the periphery has limits,
however, because a point is reached at which the compensatory mechanisms
are overwhelmed and the reserves are fully utilized; consequently pulmonary
edema develops and gas exchange becomes inefficient.
Another major conclusion drawn from previous studies is that the pul-
monary responses occurring after microembolism appear to be mediated
primarily through humoral mechanisms. These include the pulmonary va-
soconstrictor, bronchoconstrictor, and tachypneic responses and the in-
creased pulmonary vascular permeability. The humoral substances are ac-
tivated or released as a direct result of obstruction, intravascular coagula-
tion, and leukocyte and platelet activation. Some of the responses (e.g.,
tachypnea) also have a major neural component, but the neural mechanisms
may be triggered by humoral factors such as histamine and prostaglandins.
Although intravascular coagulation and leukocyte and platelet activa-
tion are important in mediating the various pulmonary responses to mi-
croembolization, the precise mediators released after the activation of these
blood components and the steps that produce the aggregation and activation
have not been clearly delineated. There is a need for a more complete un-
derstanding, of the humoral control of pulmonary vessels, airways, venti-
lation, and lung fluid balance. Pulmonary microembolism offers a unique
model because humoral factors appear to play such a dominant role in me-
diating the pulmonary responses.
I deeply appreciate the generous comments of Dr. Aubrey Taylor and Dr. Leonard Grum-
bath, who reviewed this manuscript. I thank Kathleen Roche for her patient efforts in typing
this manuscript.
The author’s research was supported by National Institutes of Health Grants HL-17355,
HL-26551, and HL-27016 and by Research Career Development Award HL-00363.
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PHYSIOLOGICAL REVIEWS

Vol. 63, No. 3, July 1983

1114 0031-9333/83 $1.50 Copyright 0 1983 the American Physiological Society

Because the pulmonary circulation receives the entire cardiac output,

The proceedings of a symposium devoted to the pathogenesis of pul-

B. Pulmonary Microembolism and Throwzbogenesis

A clot in the lumen of a pulmonary artery is usually caused by an

of intravascular coagulation by directly activating the intrinsic coagulation

C Methods of Producing Pulmonaw Microembolism

Pulmonary embolism has been produced injecting substances of various

II. PULMONARY HEMODYNAMIC RESPONSE TO MICROEMBOLIZATION

Microembolization clearly produces pulmonary hypertension without

A. Mechanisms of Increase in Pulwwnarvy Vascular Resistance

I. Eflects of mechanical obstruction

Mechanical obstruction of lung vessels after microembolization un-

pulmonary vascular bed is obstructed (103), the PVR in the experiments of

z. Active pul-q vasocmtriction

a) EvW supporting vasocmttictim The increased Ppa seen after

TABLE 1. Numbers and sizes of emboli needed to raise JX&WTUZ~

Lobar Blood clots 5.0 7 7tl

Lobular Polystyrene spheres 0.3 16,000 28,125 t 10,270

Atria1 Polystyrene spheres 0.17 89,140 t 4,260

Arterioles Lycopodium spores 28-30 pm 600-280,000 x lo6 22 x lo6

From Dalen et al. (103).

titles is obviously due to some mechanism other than simple mechanical

wave generated by contraction of the right ventricle is propelled through the

B. Factors Mediating Pulwwnaq Vasoconstriction

Sympathetic nerve stimulation causes constriction of pulmonary vessels

This lesser response appears to be related to the paucity of sympathetic

In contrast to the ambiguities surrounding the involvement of sympa-

creased concentrations in the venous blood draining embolized lungs (432)

HISTAMINE ) ( (NS) (0.003) t 1

PROSTAGLANOIN Fz, k+k

SEROTONIN (0.001) U-1 t-i

postulated this compound as the mediator of the smooth muscle contraction

source of the serotonin released after microembolization (461,492,534), and

d) Efects on pulmonary vascular compliance and blood volume. Few ob-

Decreased pulmonary perfusion persists even after dissolution of the

III. PULMONARY EDEMA AFTER MICROEMBOLIZATION

In the lung an increased extravascular water content is commonly ob-

A. Efebts of Pulmonary Microembolism on Lung Fluid Balance

Two factors have been proposed to explain the development of pulmo-

1. Pulmonary fluid and protein exchange

a) Shep studies. Pulmonary lymph (i.e., a measure of the net plasma

FIG. 2. Time course of ef-

1 ----r----l _____ J-----=----1 ______

Pla pressure, cmHzO

-60 0 60 120 180 240 300

anisms, any conclusions regarding endothelial permeability changes after

A more direct indicator of increased lung vascular permeability in this study

B. Eflects of Increasing Degree of Embolixation

FIG. 5. Relationship between

C. Reversibility of Increases in Permeability

Air Infusion PPA km Hz01

shows the effects of a similar degree of embolization (i.e., effects of similar

stantiated by the finding that pulmonary edema formed at 2 h after em-

D. Murphological Alterations in Lung Endothelium

The interendothelial junctions in pulmonary microvessels were dilated

capillary walls. In addition pulmonary edema formation was not depressed

E. Microvessels Versus Arteries as Sites of Fluid and Protein Exchange

A greater surface area is available for filtration in the pulmonary mi-

F. Hemodynumic Mechanisms Associated With Increased Permeability

The diversion of the entire cardiac output through unobstructed lung

1 ----r----l _ J-----=----1 __