Inflammation and Repair

Overview of Inflammation
Response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host
defense from the circulation to the sites where they are needed, in order to eliminate the offending agents

Innate Immunity (first responders to infection)

Steps of Inflammatory Reaction
1)
2)
3)
4)
5)

(RECOGNITION) Offending agent located in EXTRAVASCULAR tissues

(RECRUITMENT) of leukocytes and plasma proteins
ACTIVATION
TERMINATION
REPAIRMENT

Fundamental Properties
Components of Inflammatory response
blood vessels dilate=blood flow and permeability
Harmful consequences of inflammation
leaving little of no permanent damage
inflammatory reactions underlie common chronic diseases (ex. Rheumatoid
Arthritis, atherosclerosis, lung fibrosis)
may contribute to diseases primarily (metabolic, degenerative, genetic such
DM Type 2)
Local and Systemic Inflammation
the reaction is largely confined to the site of infection or damage
rare situations of disseminated reaction (ex. Sepsis), a form of SIRS
Mediators of Inflammation
produced by various cells or derived from plasma proteins
initiate and amplify the inflammatory response
Acute and Chronic Inflammation
Acute Inflammation (short duration, edema, polymorphonuclear migration)
Chronic Inflammation (longer duration, tissue destruction, mononuclear,
angiogenesis, fibrosis)
Termination of Inflammation and Initiation of Tissue Repair
mediators are broken down and dissipated
anti-inflammatory mechanisms
regeneration (replacement of surviving tissue) and scarring (filling with C.T.)

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1) HISTORICAL HIGHLIGHTS
4 Cardinal Signs of Inflammation
Rubor (redness)
Tumor (swelling)
Calor (heat)
Dolor (pain)
Functio laesa (loss of function)
2)

CAUSES OF INFLAMMATION
Infections
Tissue necrosis
ischemia (blood flow)
trauma
physical and chemical injury

Foreign Bodies
Immune reactions
also called Hypersensitivity
directed against self-antigens (Autoimmune)
associated with CHRONIC inflammation
inflammation-induced by cytokines produces by T-cells
3)

RECOGNITION OF MICROBES AND DAMAGED CELLS

Cellular receptor for microbes
membrane receptors (extracellular microbes)
endosomes (ingested microbes)
cytosol (intracellular microbes)
TLRs (Toll-like Receptors)
receptors trigger production of molecules (adhesion, cytokines,
mediators)

Sensors of cell damage

cytosolic receptors
-senses uric acid, ATP, K+ concentrations
activate Inflammasome (multiprotein cytosolic complex
that induces production of cytokine IL-1)
*IL-1=recruits leukocyte
receptor mutations (ex. autoinflammatory syndromes)=spontaneous
Inflammation

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 Other cellular receptors involved in inflammation

leukocyte express receptors
-recognized opsonized microbes
*opsonisation=coating with Ig, complement which promote
Ingestion and destruction

Circulating proteins
complement system
MBL (mannose-binding lectin)
collectins

KEY CONCEPTS
Acute Inflammation
3 Major Components:
dilation of small vessels
increased permeability
emigration of the leukocytes

liberating cytokines, lipid messengers, mediators of inflammation

efflux of plasma
1) REACTIONS OF BLOOD VESSELS IN ACUTE INFLAMMATION
The vascular reactions of acute inflammation consist of changes in the flow of blood and
the permeability of vessels, both designed to maximize the movement of plasma proteins
and leukocytes out of the circulation and into the site of infection or injury.

Escaping Fluid into Extravascular Space:

EDEMA
EXUDATE
protein concentration
Cellular debris
specific gravity
cause: vascular permeability

TRANSUDATE
protein concentration
NONE
specific gravity
cause: vascular pressure imbalances

*pus=
EXUDATE,
rich in
leukocyte
(neutrophil),

debris of dead
cells and microbes

Figure 3-2
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Changes in
Flow and

Vascular
Calibre

Vasodilation
Induced by the action of several mediators,
Notably histamine, on vasculature.
involves the ARTERIOLES
blood flow (Erythema)

Vascular Permeability
Permeability= edema
Stasis
engorgement of small vessels with slowly moving
RBCs (Vascular Congestion)
(fluid, vessel diameter=blood flow=hematocrit= Blood viscosity)
Neutrophils Accumulate
endothelial cells are activated
CAMs

Increased Vascular Permeability (Vascular Leakage)

permeability of POST-CAPILLARY
VENULES
cxn of endothelial cells= interendothelial spaces
elicited by histamine, bradykinin,
Leukotrienes, mediators
*Immediate Transient Response
-(vascular leakage 15mins-30mins)
* Delayed Prolonged Leakage (ex. Sunburn)
Endothelial Injury
resulting in endothelial necrosis and
Detachment
Trancytosis
transport of fluid and proteins through
Endothelial cell
VEGF= Intracellular Channels
life-threatening in burned patients
(Loss of Fluid)

Responses of Lymphatic Vessels and Lymph Nodes

lymph flow is increased and helps drain edema
conditions of working Lymph System:
Lymphangitis (active lymphatics)
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( active

Lymphadenitis
Lymph nodes)

enlarged (hyperplasia) of lymphoid

Follicles

KEY CONCEPTS

2)

LEUKOCYTE RECRUITMENT TO SITES OF INFLAMMATION

The changes in blood flow and vascular permeability are quickly followed by an
influx of leukocytes into the tissue.

Leukocytes also produce growth factors that aid in repair

can also injure normal bystander
The journey of leukocytes from the vessel lumen to the tissue is a multistep process
that is mediated and controlled by adhesion molecules and cytokines known as
chemokines.

Process of Emigration:
1) Margination, rolling and adhesion to endothelium
2) Migration across the endothelium
3) Migration into tissues by chemotaxis

Leukocyte Ahesion to Endothelium

leukocytes toward the wall of the vessel
more white cells assume a peripheral position along
the endothelial surface (Margination)
leukocytes adhere transiently
detach and bind again (Rolling)
The attachment of leukocytes to endothelial cells is
mediated by complementary adhesion molecules on the
two cell types whose expression is enhanced by cytokines
*Cytokines=secreted by sentinel cells (macrophage,
Mast cells, endothelial cells)
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Molecules

involved:
Selectins (rolling)
Note: Ligand: Sialyl-Lewis X-modified glycoprotein
(leukocyte)
Receptor: selectins (endothelium)
the ligands for selectins are sialylated
oligosaccharides bound to mucin-like
glycoprotein backbones.
regulated by cytokines (TNF, IL-1,
Chemokines)
*Chemokines=chemoattractant
TNF and IL-1 act on endothelial cells
ADJACENT to the infection, expression
Of numerous adhesion molecules.

Weibel-Palade bodies (stores selectins,

Inside endothelial cell granules)
low-affinity interactions
easily disrupted by flowing blood
thus begin to roll along the endothelium
Integrins (adhesion)
Note: Ligand: Integrin-ligand (endothelium)
Receptor: Low Affinity State Integrins (leukocyte)
firm
leukocytes normally express integrins in
a LOW affinity state
chemokines bind to and activate the
Rolling leukocytes
integrin conversion(affinity to affinity)
results in firm integrin-mediated binding
Of leukocytes to the endothelium

Leukocyte Migration Through Endothelium

The next step in the process of leukocyte recruitment is migration
Of the leukocytes through the endothelium (Transmigration or
Diapedesis)
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 chemokines act on the adherent leukocytes

migrate through interendothelial spaces toward the chemical
Concentration gradient
where the chemokines are being produced
leukocytes pierce the basement membrane, by secreting
(Collagenases)
toward the chemotactic gradient

Chemotaxis of Leukocytes
After exiting the circulation, leukocytes move in the tissues toward
the site of injury (Chemotaxis).
most common EXOgenous agents are bacterial products
(N-formylmethionine terminal amino acid)
most common ENDOgenous agents
cytokines
complement system
Arachidonic acid (AA) metabolites

agents bind to G protein-coupled receptors

activation of second messengers
Effect: leukocyte moves
polymerization of actin (leading)
localization of myosin (back)
moves by extending filopodia that pull the back of the cell in
the direction of extension
The nature of the leukocyte infiltrate varies with the age of the
Inflammatory response and type of stimulus.
neutrophil predominate (first 6-24 hrs)
replaced by monocytes (24-48 hrs approx. 1-2 days)
after entering tissues, neutrophils are short-lived; undergo
APOPTOSIS and disappear within (6-24hrs)
Note: early inflammation (neutrophil)
Prolonged inflammation (monocyte)
agents that block TNF (anti-chronic inflammation)

Figure 3-4
KEY CONCEPTS
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3) PHAGOCYTOSIS AND CLEARANCE OF OFFENDING AGENT

Recognition of microbes or dead cells induces several responses in leukocytes (leukocyte
Activation)

(activaton=cytosolic Ca2+=enzymes)
the functional responses that are most important for destruction of
microbes and other offenders are phagocytosis and intracellular
killing.
Phagocytosis
Steps:
Recognition and attachment (opsonisation and
recognition)
Engulfment
Killing or degradation
1) Recognition
Mannose receptors, scavenger receptors, and receptors
for various opsonins bind and ingest microbes.
*mannose receptors (binds terminal mannose and
Fucose residues (sugar on microbial cell
walls), recognize microbes and NOT host
cells
*Scavenger receptors
(bind and mediate endocytosis
of oxidized or acetylated LDL particles that
can no longer interact with its LDL receptor
* Mac-1 (CD11/CD18)-are integrins that bind
microbes for phagocytosis
phagocytosis is greatly enhanced when microbes are
Opsonized (coated)
Major Opsonins:
IgG antibodies
C3b breakdown products
mannose-binding lectin
2) Engulfment
extensions of cytoplasm (pseudopods)
phagosome
phagocytosis is dependen on polymerization of actin
filaments

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3) Killing/Degradation
Killing of microbes is accomplished by ROS and
reactive nitrogen species, mainly derived from (NO),
and these as well as lysosomal enzymes destroy
Phagocytosed debris.
killing mechanisms are normally sequestered in
lysosomes
ROS (O2-H2O2OH-)
produced by enzyme (NADPH oxidase)
also known as phagocyte oxidase
oxidized NADPH, reduced OXYGEN
(products: NADP+, O2- )
part of Respiratory Burst
produced within the lysosome and
Phagolysosome
H2O2 is NOT able to efficiently kill
microbes by itself
neutrophils contain MPO
(Myeloperoxidase), converts H2O2
to OCL2-, anti-microbial
H2O2-MPO-halide system
implicated in tissue damage
accompanying inflammation

Nitric Oxide (NOONOO-)

NO from arginine
produced by NOS (Nitric Oxide
Synthase)
3 Types of NOS (ONLY iNOS) is
involved in microbial killing
induced when macrophages and
neutrophils are activated by cytokines
produces Peroxynitrite (microbicidal)
Lysosomal Enzymes and Other Lysosomal Proteins
Neutrophil Granules
Specific
Azurophil
smaller
larger
secondary
primary

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Important Proteins:
MPO, elastase,
lysozyme defensins

Important Proteins:
Collagenase, plasminogen
activator, histaminase
Granule Enzymes
Acid Protease
Neutral Protease
Degrade
bacteria
Degrade ECM

and debris
components
degrade virulence factors of bacteria and

Neutrophil elastase has been shown to

thus combat bacterial infections.

Protease (ex. Elastase) are
controlled by antiproteases
ex. (1-antitrypsin)
deficiency:
(Protease= Cellular Proteins)

4) Leukocyte-Mediated Tissue Injury

prolonged host response
autoimmune
allergic diseases
The mechanisms by which leukocytes damage
normal tissues are the same as the mechanisms
involved in antimicrobial defense.

5) Other Functional Responses of Activated Leukocytes

Lymphocytes that produce IL-17
*IL-17 induces chemotaxis
Deficiency: cold abscess

4) TERMINATION OF THE ACUTE INFLAMMATORY RESPONSE

the mediators of inflammation are produced in rapid bursts, only as
long as the stimulus persists, have short half-lives, and are degraded after
their release
include a switch in the type of arachidonic acid metabolite produced,
from proinflammatory leukotrienes to anti-inflammatory lipoxins
(cholinergic discharge) that inhibit the production of TNF in
macrophages
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KEY

CONCEPTS
5) MEDIATORS OF INFLAMMATION
The mediators of inflammation are the substances that initiate and regulate
inflammatory reactions.

Properties, Production and Action of Mediators

The most important mediators of acute
inflammation are vasoactive amines, lipid products
(PG, Leukotrienes),cytokines (chemokines), and
products of complement activation.
Mediators are either secreted by cells or generated
from plasma proteins. The major cell types that
produce mediators of acute inflammation are the
sentinels.
Active mediators are produced in response to
various stimuli
Most of the mediators are short-lived
One mediator can stimulate the release of other
mediators.

1) Amines: Histamine and Serotonin

first mediators to be released during inflammation
Histamine
Causes dilation of arterioles and
increases the permeability of venules.
mast cells secrete Histamine,
also found in basophils and
platelets.
stored in mast cell granules and
is released by degranulation
Neuropeptides (Substance P)
cytokines may trigger the
release of histamine
H1 receptors
contraction of smooth muscles

Serotonin (5-hydroxytryptamine)
present in platelets
vasoconstrictor
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 unknown function

2) Arachidonic Acid Metabolites

The lipid mediators prostaglandins and leukotrienes
are produced from arachidonic acid (AA) present in
membrane phospholipids, and stimulate vascular and
cellular reactions in acute inflammation. Drugs:
Non-selective COX-inhibitors (NSCI), Lipox
Inhibitors, Corticosteroids, Leukotriene receptor
antagonists
Prostaglandins (PG)
Produced by sentinel cells, involved in
Vascular and SIRS
PGD2 is the major PG made by
Mast cells
Arachidonic Acid Metabolites Action in Inflammation
Action
Vasodilation
Vasoconstriction

Eicosanoid
All PGs
TX, Leukotrienes
(C4,D4,E4)
Vascular Permeability
Leukotrienes (C4,D4,E4)
Chemotaxis, Adhesion
Leukotrienes B4 ,HETE
chemoattractant
pathogenesis of pain and fever
in inflammation
PGE2 is hyperalgesic
makes the skin
hypersensitive to
painful stimuli
Leukotrienes
Produced by leukocytes and mast cells
by the action of Lipoxygenase and are
involved in vascular and smooth muscle
reactions and leukocyte recruitment.
Lipoxins
Generated from AA by the lipoxygenase
pathway, but unlike PG and Leukotri.
the lipoxins suppress inflammation by
inhibiting the recruitment of leukocytes.

Figure 3-10
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3) Cytokines and Chemokines

Proteins produced by many cell types (principally
Activated lymphocytes, macrophages, and dendritic
cells, but also endothelial, epithelial, and connective
tissue cells) that mediate and regulate immune and
inflammatory reactions.
TNF and IL-I
Serve critical roles in leukocyte recruitment by
promoting adhesion of leukocytes to endothelium
and their migration through vessels.
Endothelial activation
Activation of leukocytes and other cells
Systemic acute-phase response
(fever, catabolism, loss of appetite
which lead to Cachexia)
*Cachexia-pathologic state of
weight loss, anorexia,
chronic ifections and
neoplasm
TNF antagonists have been remarkably effective in
the treatment of chronic inflammatory diseases.
Chemokines
Family of small (8 to 10 kD) proteins that act
primarily as chemoattractants for specific types
of leukocytes.
In Acute Inflammation
stimulate leukocyte attachment to
endothelium, increase affinity of integrin
chemotaxis
Maintenance of Tissue Architecture.

Table 3-6
4) Complement System
Is a collection of soluble proteins and membrane
receptors that function mainly in host defense against
microbes and in pathologic inflammatory reactions.
numbered C1 through C9
vascular permeability, chemotaxis, opsonisation
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present INACTIVE forms in plasma

the critical step in complement activation is the
Proteolysis of the third and most abundant
Component (C3)
Pathways of C3 Activation:
Classical
triggered by fixation of C1 to opsonized
antigen (antibodies: IgG or IgM)
Alternative
triggered by non-opsonized antigen
(ex. Endotoxin and LPS)
Lectin
happens when mannose-binding lectin
binds to carbohydrates on microbes
and directly activates C1
All (3) pathways lead to the formation of
active enzyme called C3 convertase,
which splits C3 into two functionally
distinct fragments (C3a and C3b)
Tip: C#a release
C#b attached to the cell surface
Function of Complement System:
Inflammation
stimulate histamine
release from mast cells
(Anaphylatoxins)
Opsonization and Phagocytosis
Cell Lysis
deposition of MAC on
cells make these cells
permeable to water and
ions and results in
death (lysis) of the cell

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