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Outline of Lecture

Acute  and  Chronic Inflammation


What is Inflammation?

The protective vascular and connective tissue response to tissue injury




Start repair process

Acute and chronic forms

Cardinal Signs of Inflammation

Rubor : Redness – Hyperaemia.

Calor  : Warm – Hyperaemia.

Dolor  : Pain – Nerve, Chemical med.

Tumor: Swelling – Exudation

Loss of Function:


Acute Inflammation

Short duration: minutes, hours, few days

Exudation of fluid and plasma proteins leading to edema

Emigration of white blood cells, mostly neutrophils to site of injury

Rubor, tumor, dolor, calor


Chronic Inflammation

Longer duration than acute phase

Lymphocytes and macrophages

Proliferation of blood vessels, fibrosis, and presence of necrosis


Acute Inflammation

Immediate and early response to tissue injury (physical, chemical, microbiologic, etc.)


Vascular leakage and edema

Leukocyte emigration (mostly PMNs)


Acute Inflammation

Vascular Events


Vasodilation :-

Accounts for warmth and redness (rubor, calor)

Opens microvascular beds

Increased intravascular pressure causes an early transudate (protein-poor filtrate of plasma) into interstitium (vascular permeability still not increased yet) – tumor


Vascular Leakage

Vascular permeability (leakiness) commences

transudate gives way to exudate (protein-rich)

increases interstitial osmotic pressure contributing to edema (water and ions)


Vascular leakage

Five 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 (not arterioles, capillaries)


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, (cont’d) or some bacterial toxins (delayed prolonged 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


Certain mediators (VEGF) may cause increased transcytosis via intracellular  vesicles which travel from the luminal to basement membrane surface of the endothelial cell


All or any combination of these events may occur in response to a given stimulus


Leukocyte cellular events

Leukocytes leave the vasculature routinely through 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 settle-out of the central flow column and “marginate” along the endothelial surface

Early rolling adhesion mediated by selectin family of adhesion molecules


Endothelial cells and leukocytes have complementary surface adhesion molecules which briefly stick and release causing the leukocyte to roll along the endothelium like a tumbleweed until it eventually comes to a stop as mutual adhesion reaches a peak


Rolling comes to a stop and adhesion results

Other sets of adhesion molecules participate, such as the integrins

Ordinarily down-regulated or in an inactive conformation

Transmigration (diapedesis)

Occurs after firm adhesion within the systemic venules and pulmonary capillaries via other adhesion molecules (CD31)

Must then cross basement membrane



Transmigration (diapedesis)

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)


Leukocytes follow chemical gradient to site of injury (chemotaxis)

Soluble bacterial products

Complement components (C5a)

Cytokines (chemokine family such as Il-8)

LTB4 (AA metabolite)


Extend pseudopods with expressing surface adhesion molecules (integrins) that bind ECM during chemotaxis

Phagocytosis and Degranulation

Once at site of injury, leukocytes:

Recognize and attach

Engulf (form phagocytic vacuole)

Kill (degrade)

Recognition and Binding

Opsonized by serum complement, immunoglobulin (C3b, Fc portion of IgG)

Corresponding receptors on leukocytes (FcR, CR1, 2, 3) leads to binding


Phagocytosis and Degranulation

Triggers oxidative burst, engulfment and formation of vacuole which fuses with lysosomal granule membrane (phagolysosome)

Granules discharge within phagolysosome and extracellularly (degranulation)


Oxidative Burst

Reactive oxygen species formed through oxidative burst that includes:

increased oxygen consumption


increased glucose oxidation

formation of superoxide ion

2O2 +  NADPH  ® 2O2-rad  +  NADP+  +  H+                                          (NADPH oxidase)

O2-rad  +  2H   H2O2  (dismutase)

Reactive Oxygen Species

Hydrogen peroxide alone insufficient

MPO (azurophilic granules) converts hydrogen peroxide to HOCl , an oxidant/antimicrobial agent (“bleach”)

Degradation and Clean-up

Reactive end-products only active within phagolysosome

Hydrogen peroxide broken down to water and oxygen by catalase

Dead microorganisms degraded by lysosomal acid hydrolases

Leukocyte-induced Tissue Injury

There is a cost, destructive enzymes may enter extracellular space when:

premature degranulation

frustrated phagocytosis (large, flat)

membranolytic substances (urate crystals)

persistent leukocyte activation (RA, emphysema)

Defects of Leukocyte Function

Defects of adhesion:

LFA-1 and Mac-1 (integrins) subunit defects lead to impaired adhesion (LAD-1)

recurrent bacterial infections with impaired wound healing

absence of sialyl-Lewis X, and defect in E- and P-selectin sugar epitopes (LAD-2)

clinically milder than LAD-1, but recurrent bacterial infections


Defects of chemotaxis/phagocytosis:

microtubule assembly defect leads to impaired locomotion and lysosomal degranulation

neutropenia, defective neutrophil degranulation, delayed microbial killing, recurrent bacterial infections

Defects of microbicidal activity:

deficiency of NADPH oxidase that generates superoxide, therefore no oxygen-dependent killing mechanism (Chronic Granulomatous Disease)

recurrent bacterial infections

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