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Chapter 17

Inflammation:
Understanding Its Role In
Acute And Chronic Disease

History
Inflammation has been recognized as a component of the
bodys response to injury from the time of the Egyptians
Celsus of Rome documented the four cardinal signs of
inflammation.
It became clear that inflammation is an integral part of a
persons innate immunity: mechanism of nonspecific first
response to pathogens, toxins, pollutants, and inhalants.
Evidence showed that chronic inflammation exists and that it
can play a significant role in cardiovascular disease and
Alzheimers Dementia (among others).
Inflammation is also a component in injuries from
environmental hazards.

What is Inflammation?
It is the bodys local vascular and cellular response to
injury caused by factors that invade and injure the body
from the outside (exogenous factors) or factors within the
body (endogenous factors) that result in cellular or tissue
injury.
It is part of an innate immune response: requires no
previous exposure to the insult.
Response is rapid

Acute Inflammation

Short-term (hours or days).


Abrupt in onset.
Nonspecific response.
5 main symptoms:
1.
2.
3.
4.
5.

Warmth
Redness in area of injury
Pain (throbbing)
Localized swelling
Loss of function in the site of injury

Vascular Response
Clinical signs of acute inflammation are due to an initial
vascular response localized to the area of injury
The increased blood flow and dilation of vessels
(increased permeability) is caused by relaxation of
vascular smooth muscle.
Stimulation is immediate in response to direct injury or
IgE-mediated effects on tissue mast cells - cause cells to
release Histamine.
Histamine is the predominate stimulus to vascular
response, but there are also other mediators that come
from plasma.

Cellular Response - Neutrophils

Neutrophils are the first line of defense against foreign invaders.


Predominant cell type in normal circulation.
They are uniquely adapted to their task due to their structure.
Have a short life - replaced rapidly from bone marrow.
Arrive to site of injury quickly - become maximal within 24 - 48
hours; however, the secondary damage to tissue can also be
significant.
The second phase of acute inflammatory response is marked by
the accumulation of a cellular exudate of neutrophils within the
area of injury.
Neutrophils engage in phagocytosis (engulf matter to prevent
further harm).

Phagocytosis
Matter is engulfed within a vacuole, which then fuses
with a lysosome to form phagolysosome. Bacteria is then
killed by lysosomal and protease enzymes.
Opsonins: factors that coat particulate matter to enhance
phagocytosis.
- i.e. matter is associated with ligands that can bind to
receptors on the surface of neutrophils.
Phagocytosis can occur in anaerobic environment,
however, the microbicidal activity of neutrophils is much
greater in presence of oxygen.

Cellular Response - Monocytes &


Macrophages

Monocytes - in circulation.
Macrophages - in tissue.
Are phagocytic (ameboid motion).
Contain the same receptors for Toll-ligands and opsonins
that are expressed on neutrophils.
- Toll-like receptors bind common antigens, such as LPS
in walls of gram negative bacteria.
- Binding activate leukocytes and stimulates release of
proinflammatory cytokines.

Cellular Response - Monocytes &


Macrophages
Macrophages:
- Have longer life (1 or more months)
- Antimicrobial metabolism produces oxygen and free
radicals (nitric oxide).
- Process foreign material for presentation to lymphocytes.

Monocytes:
- circulate in blood and differentiate into macrophages in the
tissue.
- 2nd wave of cells at sites of injury in acute inflammation.

Migration of Neutrophils and Monocytes


Migrate out of blood and into injured tissue by margination,
adherence, and emigration.
Early mediators cause neutrophils, monocytes, and endothelial
cells to synthesize selectins (expressed on cell surfaces).
Selectins cause contact between cells in blood and surface of
endothelial cells.
Prolonged contact stimulates synthesis and expression of
integrins (bind and anchor neutrophils & monocytes to venule).
Anchored cells become exposed and bound to chemoattractants (mediators) - causes cells to move into tissue.
Major chemo-attractants included C5a component,
Leukotriene B4, and chemokines.

Exudate
Suppurative (pus)
It is the accumulation of protein-rich fluid exudate
(neutrophils and necrotic tissue).
Recognized hallmark of infection.
Other exudates are named by their major component:
- Serous (edema fluid)
- Fibrinous (fibrin)
- Hemorrhagic (blood)

Manifestation and Complications of


Acute Inflammation
Danger of acute inflammation: damaging tissue so
that function is lost or that associated infection can
extend beyond the localized area of injury to the rest
of the body.
Two distinctive manifestations include formation of
abscesses or ulcers.

Abscesses and Ulcers


Abscess:
- Compartmentalized collection of suppurative exudate and tissue
necrosis enclosed by tissue.
- Hard to heal - inner core is dead tissue (no vascular supply).
- Risk: on-going tissue injury and widespread infection (sepsis).

Ulcer:
- localized site of inflammation and necrosis at the surface of skin or
the inner surface of an organ.
- Sufficient damage causes gap/hole in tissue surface.
- Non-removed infectious agents can penetrate deeper into tissue
and cause systemic infection.

Systemic Signs of Inflammation


Leukocytosis:
- Increase in circulating leukocytes.
- Occurs within hours of stimulus.
- Mobilized from bone marrow.
- Granulopoiesis: process when bone marrow generates
new cells in proportion to demand.

Fever:
- Results from stimulation of the hypothalmic
thermoregulatory center by cytokines released from
activated macrophages and other cells.

Healing and Repair


Three overlapping phases (mediated by cytokines):
1. Influx of macrophages and clearance of debris.
2. Influx and regeneration of endothelial cells and new
vessel formation (angiogenesis).
- Dehiscence: time when regenerating tissue is least strong and
most in danger of tearing open.

3.

Proliferation of fibroblasts and myofibroblasts that


produce a progressive accumulation of collagen, as
required by the extent of the wound.
- Collagen and scar hold tissue together against forces that might
pull it apart.

Healing and Repair - Contd


When granulation tissue is present, which is the loose
matrix of regenerating connective tissue, the wound is
organizing or organized.
Wounds are healed by first or second intention:
-First: the edges of the wound can be brought together,
usually by stitches (little tissue regeneration).
-Second: a wound that is so large that the edges cannot be
approximated, scar formation is the inevitable result.

Healing without loss of function or scar requires that the


tissue remains intact, so that regenerating cells can be
oriented in a way that allows them to function properly.

Causes for Delay or Absence of Healing


Host factors that prevent the regeneration or function
of native and new connective tissue cells.
Large injury area.
Stimulus for inflammation cannot be removed.
Inadequate blood supply (diabetes).
Malnutrition (insufficient protein)
Suppression of the immune response.
Vitamin C deficiency (inadequate collagen synthesis).

Chronic Inflammation
Occurs when inciting stimuli (chronic infections,
tissue irritants, or altered proteins) for inflammation
cannot be removed from the body.
Prolonged activation of the inflammatory response.
Lymphocytes and macrophages predominate.
Macrophage chemo-attractant production favors
migration of lymphocytes to injury area, rather than
neutrophils (acute).
Ongoing tissue injury incites an ongoing effort to heal
- causes a progressive increase in the accumulation
of collagen and scar formation in the tissue.

Chronic Inflammation - Contd


Associated with many major chronic organ system diseases.
The progressive loss of functional tissue and the increase of scar
tissue in the organ impact on the function of the organ and ultimately
results in its failure.
Examples include:
- Chronic Hepatitis caused by Hepatitis C virus infecting the liver; can
lead to Cirrhosis. Hepatitis C virus also causes portal hypertension
and hepatocellular carcinoma.
- Atherosclerosis.
- Chronic Bronchitis.
- Collagen vascular disease (rheumatoid arthritis).
- Inflammatory bowel disease.

Evidence of Chronic Inflammation

Tissue injury and scar.


An infiltrate of lymphocytes.
Lesser numbers of macrophages.
Occasional antibody-producing plasma cells.
Granuloma:
- A distinctive inflammatory infiltrate that contains an aggregate
of macrophages surrounded by lymphocytes.
- When activated by lymphocyte cytokines, the macrophages
become epithelioid.
- Form when macrophages cannot kill certain organisms or
degrade certain proteins that are resistant to them.

Causes of Chronic Inflammation


Associated with Granulomas
Mycobacterium tuberculosis
- Caseous necrosis
- Latent Mycobacteria can become reactivated in
conditions of immunosupression.

Sarcoidosis
Fungal infections
Parasitic infections
Inorganic substances

Inflammation and the Shifting Burden


of Disease
Infectious diseases accounted for the majority of Disability
Adjusted Life Years (DALYS) before modern medicine.
Progression in medicine and living conditions increased lifespan, but also increased the rates of chronic diseases.
Currently, chronic disease is the major source of DALYS.
Its important to understand the risk factors, disease
mechanisms, and health consequences of chronic conditions.
Inflammation is an example of an evolutionary adaptive
response that has become maladaptive in todays environment.
Chronic inflammation is quiet injurious and contributes to many
chronic conditions (heart attack, Alzheimers, cancer).

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