Inflammation

By Dr. Asma Inam

Definition

❑ Inflammation is a non specific, localized immune reaction of

the organism, which tries to localize the pathogen agent.
Many consider the syndrome a self-defense mechanism.

❑ It consists of vascular, metabolic, cellular changes, triggered

by the entering of pathogen agent in healthy tissues of the
body.

❑ Acute, subacute and chronic forms.

Etiology

Exogenous causes:
⚫ Physical agents

▪ Mechanical agents: fractures, foreign particles, etc.

▪ Thermal agents: burns, freezing
⚫ Chemical agents: toxic gases, acids, bases
⚫ Biological agents: bacteria, viruses, parasites
Endogenous causes:
⚫ Circulation disorders: thrombosis, infarction,
hemorrhage
⚫ Metabolic products deposals – uric acid, urea
Acute Inflammation
⚫ Immediate and early response to tissue injury (physical,
chemical, microbiologic, etc.)
➢ Classical signs of acute inflammation are:

⚫ rubor (redness)
⚫ tumor (swelling)
⚫ calor (heat)
⚫ dolor (pain)
⚫ functio laesa, or loss of function (In the second century AD,
the Greek physician Galen added this fifth cardinal sign)
Three essential features of acute inflammation are:

1. Hyperaemia
2. Exudation of fluid
3. Emigration of leucocytes
 Injury

Direct effect on Nervous reaction

vessels
Damaged cells

Chemical mediators

Vascular Dilatation
The Vascular Response
⚫ Vasoconstriction (momentary constriction of small blood
vessels in the area).
⚫ The mechanism of spasm is nervous .

⚫ Vasodilation
⚫ Dilation of arterioles and capillaries (redness = rubor).

⚫ Blood flow increases and gives pulsate sensation.

⚫ Active hyperemia in skin territory and increased

metabolism leads to higher local temperature (heat =
calor).
➢ Progressively fluid move into the tissues (increased
vascular permeability and structural alteration of blood
vessels) and cause swelling (tumor), pain, and impaired
function.

➢ The exudation or movement of the fluid out of the

capillaries and into the tissue spaces dilutes the offending
agent. As fluid moves out of the capillaries, stagnation of
flow and clotting of blood in the small capillaries occurs at
the site of injury.This aids in localizing the spread of
infectious microorganisms, if case.
Vascular leakage

⚫ Four mechanisms known to cause vascular leakiness

⚫ Histamines, bradykinins, leukotrienes

Cause an early, brief (15 – 30 min.) immediate transient
response in the form of endothelial cell contraction that
widens intercellular gaps of venules.
Vascular leakage

⚫ Cytokine mediators (TNF, IL-1) induce endothelial cell

junction retraction through cytoskeleton reorganization (4
– 6 hrs post injury, lasting 24 hrs or more)

⚫ Severe injuries may cause immediate direct endothelial

cell damage (necrosis, detachment) making them leaky
until they are repaired (immediate sustained response), or
may cause delayed damage as in thermal or UV injury,
Vascular Leakage

⚫ Marginating and endothelial cell-adherent leukocytes may

pile-up and damage the endothelium through activation
and release of toxic oxygen radicals and proteolytic
enzymes (leukocyte-dependent endothelial cell injury)
making the vessel leaky.
Leukocytes vascular events
⚫ Leukocytes leave the vasculature routinely by the following
sequence of events:
⚫ Margination and rolling

⚫ Adhesion and transmigration

⚫ Chemotaxis and activation

⚫ They are then free to participate in:

⚫ Phagocytosis and degranulation

⚫ Leukocyte-induced tissue injury

Margination and Rolling
⚫ With increased vascular permeability, fluid leaves the vessel
causing leukocytes to marginate along vessel wall

⚫ Endothelial cells and leukocytes have complementary

surface adhesion molecules which briefly stick and release
causing the leukocyte to roll along the endothelium.

⚫ E- selectin, L- selectin and P- selectin

➢ Other sets of adhesion molecules participate:
⚫ Endothelial: ICAM-1, VCAM-1

⚫ Leukocyte: LFA-1, Mac-1, VLA-4

Adhesion
⚫ Rolling comes to a stop and adhesion results
(ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-4)
⚫ Ordinarily down-regulated or in an inactive conformation, but
inflammation alters this Other sets of adhesion
molecules participate:
⚫ Endothelial: ICAM-1, VCAM-1
⚫ Leukocyte: LFA-1, Mac-1, VLA-4
Transmigration (diapedesis)
⚫ Occurs after firm adhesion within the systemic venules and
pulmonary capillaries via PECAM –1 (CD31)
⚫ Must then cross basement membrane.

⚫ Early in inflammatory response mostly PMNs, but as cytokine

and chemotactic signals change with progression of
inflammatory response, alteration of endothelial cell
adhesion molecule expression activates other populations of
leukocytes to adhere (monocytes, lymphocytes, etc)
Chemotaxis
⚫ Leukocytes follow chemical gradient to site of injury
(chemotaxis)
⚫ Soluble bacterial products

⚫ Complement components (C5a)

⚫ Cytokines (chemokine family e.g., IL-8)

⚫ LTB4 (AA metabolite)

⚫ Leukocytes:
⚫ extend pseudopods with overlying surface adhesion
molecules (integrins) that bind ECM during chemotaxis
⚫ Undergo activation:
⚫ Prepare AA metabolites from phospholipids
⚫ Prepare for degranulation and release of lysosomal
enzymes (oxidative burst)
⚫ Regulate leukocyte adhesion molecule affinity as needed
Phagocytosis and
Degranulation
⚫ Once at site of injury, leukocytes:
⚫ Recognize and attach pathogen

⚫ Engulf (form phagocytic vacuole)

⚫ Kill (degrade)
Factors influencing phagocytosis are:
❑ Opsonins

❑ Fraction of complement system

❑ Physical state of cellular environment.

Phagocytosis and Degranulation through oxidative burst.

➢ Therefore, PMNs can kill by lipid/protein peroxidation.

⚫ Other antimicrobials in leukocyte granules:

⚫ Bactericidal permeability increasing protein (BPI)

⚫ Lysozyme

⚫ Defensins (punch holes in membranes)

Phagocytosis
Chemical mediators
⚫ Plasma-derived:
⚫ Complement, kinins, coagulation factors

⚫ Many in “pro-form” requiring activation (enzymatic

cleavage)
⚫ Cell-derived:
⚫ Preformed, sequestered and released (mast cell histamine)

⚫ Synthesized as needed (prostaglandin)

Chemical mediators
⚫ May or may not utilize a specific cell surface receptor for
activity
⚫ May also signal target cells to release other effector
molecules that either amplify or inhibit initial response
(regulation)
⚫ Are tightly regulated:
⚫ Quickly decay (AA metabolites), are inactivated
enzymatically (kininase), or are scavenged (antioxidants)
Specific mediators
⚫ Vasoactive amines
⚫ Histamine: vasodilation and venular endothelial cell
contraction, junctional widening; released by mast cells,
basophils, platelets in response to injury (trauma, heat),
immune reactions (IgE-mast cell FcR), anaphylatoxins (C3a,
C5a fragments) and cytokines (IL-1, IL-8)

⚫ Serotonin: similar to those of histamine; platelet

granules; release triggered by platelet aggregation
⚫ Plasma proteases
⚫ Clotting system,kinins and complement
Specific Mediators
⚫ Arachidonic acid metabolites (eicosanoids)
⚫ Prostaglandins and thromboxane:

via cyclooxygenase pathway; cause vasodilation and

prolong edema; but also protective (gastric mucosa); COX
blocked by aspirin and NSAIDS.
⚫ Leukotrienes:
via lipoxygenase pathway; are chemotaxins,
vasoconstrictors and bronchospasm.
⚫ PAF (platelet activating factor)
⚫ Derived also from cell membrane phospholipid, causes
vasodilation, increased vascular permeability, increases
leukocyte adhesion.
The cyclooxygenase and lipoxygenase
pathways
More specific mediators
⚫ Cytokines
⚫ Protein cell products that act as a message to other
cells, telling them how to behave.
⚫ IL-1, TNF- and -, IFN- are especially important in
inflammation.
⚫ Increase endothelial cell adhesion molecule
expression, activation and aggregation of PMNs, etc.
Specific mediators
⚫ Nitric Oxide
⚫ short-acting, soluble, free-radical gas with many functions
⚫ Produced by endothelial cells, macrophages, causes:
⚫ Vascular smooth muscle relaxation and vasodilation
⚫ Kills microbes in activated macrophages.
⚫ Lysosomal components
➢ Leak from PMNs and macrophages.
➢ Acid proteases and neutral proteases like?
Possible outcomes of acute
inflammation
⚫ Complete resolution
⚫ Scarring (fibrosis)
⚫ Abscess formation occurs with some bacterial or fungal
infections
⚫ Progression to chronic inflammation
Inflammation
⚫ Stage I:
⚫ Following an insult, local cytokine is produced with the goal
of inciting an inflammatory response, promoting wound
repair and recruitment of the reticular endothelial system.
⚫ Stage II:
⚫ Small quantities of local cytokines are released into
circulation to improve the local response. This leads to
growth factor stimulation and the recruitment of
macrophages and platelets. The goal is homeostasis.
⚫ Stage III:
⚫ If homeostasis is not restored, a significant systemic
reaction occurs. The cytokine release leads to destruction
rather than protection. A consequence of this is the
subsequent loss of circulatory integrity.
Resolution of inflammation
⚫ The inflammatory response must be actively terminated
when no longer needed.
⚫ Resolution of inflammation occurs by:
⚫ Short half-life of inflammatory mediators in vivo;
⚫ Production and release of (TGF) beta
⚫ Downregulation of pro-inflammatory molecules, such as
leukotrienes;
⚫ Upregulation of anti-inflammatory molecules such as the
Interleukin 1 receptor antagonist or the soluble tumor
necrosis factor receptor;
⚫ Apoptosis of pro-inflammatory cells;
⚫ Downregulation of receptor activity by high concentrations
of ligands;
⚫ IL-4 and IL-10 are cytokines responsible for decreasing the
production of TNF-a, IL-1, IL-6, and IL-8.
Chronic Inflammation

➢ In acute inflammation, if the injurious agent persists then

chronic inflammation will ensue
➢ Inflammation lasting many days, months or even years.
➢ Characterised by the dominating presence of
macrophages in the injured tissue. These cells are powerful
defensive agents of the body, but the toxins they release
(including reactive oxygen species) are injurious to the
organism's own tissues as well as invading agents.
➢ Consequently, chronic inflammation is almost always
accompanied by tissue destruction.