MECHANISM OF

INFLAMMATION
LECTURER:DR.AQSA AZIZ
 OBJECTIVES
• At the end of unit each learner will be able to:
1. Discuss the purpose of inflammation
2. Describe physiological mechanisms involved in
the production of five cardinal signs of
inflammation
3. Differentiate hemodynamic and cellular phases of
inflammatory response
4. Differentiate between chronic and acute
inflammation
Introduction

Inflammation is defined as the local response of living

mammalian tissues to injury due to any agent. injury
due to any agent.
Body defense reaction – eliminate or limit the spread of
injurious agent
Cause of Inflammation

1. Infective agents like bacteria, viruses and their toxins, fungi, parasites.
Immunological agents like cell-mediated and antigen antibody reactions.
2. Physical agents like heat, cold, radiation, mechanical trauma.
3. Chemical agents like organic and inorganic poisons.
4. Inert materials such as foreign bodies
Cause of Inflammation

• A. Exogenous • B. Endogenous
• Mechanical • Circulatory disorder, hypoxia
• Physical • Endogenous protease release
• Chemical • Immuncomplex formation
• Biological
Inflammation
 Protective response by the body to variety of etiologic agents, while infection is
invasion into the body by harmful microbes and their resultant ill-effects by toxins
 2 basic processes with some overlapping – early inflammatory response–– later
followed by healing
 Sometimes it causes considerable harm to the body as well
anaphylaxis to bites by insects or reptiles, drugs, toxins,
atherosclerosis, chronic rheumatoid arthritis,
fibrous bands,
adhesions in intestinal obstruction.
• Inflammation is a response intended to eliminate the initial cause
of cell injury, remove the damaged tissue, and generate new
tissue.
• It accomplishes this by destroying, enzymatically digesting,
walling off, or otherwise neutralizing the harmful agents such as
toxins, foreign agents, or infectious organisms.
• These processes set the stage for the events that will eventually
heal the damaged tissue. Thus, inflammation is intimately
interwoven with the repair processes that replace damaged tissue
or fill in the residual defects with fibrous scar tissue
SIGNS OF INFLAMMATION
5 cardinal signs
I. – rubor (redness);
II. – tumor (swelling);
III. – calor (heat);– calor (heat);
IV. – dolor (pain)
V. functio laesa (loss of function)
TYPES OF INFLAMMATION

• Mainly of 2 types i.e. acute and chronic

• Acute Inflammation – short duration – represents the early body reaction-
followed by healing
• Chronic inflammation – longer duration – causative agent of acute
inflammation persists for a long time
• Another variant, Chronic active inflammation : stimulus is such that it
induces chronic inflammation from the beginning
CHARACTERISTICS OF INFLAMMATIONS
ACUTE INFLAMMATION

The main features of acute inflammation are:

accumulation of fluid and plasma at the affected site;
intravascular activation of platelets;
polymorphonuclear neutrophils as inflammatory cells.
ACUTE INFLAMMATION

• Divided into following two events

– Vascular events
– Cellular events–
These 2 events are followed intermittently by release of mediators of acute
inflammation.
A. VASCULAR EVENTS

• Alteration in the microvasculature

• This is again divide in 2 phases
I. Hemodynamic changes
II. Changes in the vascular permeability
1. Hemodynamic changes

1. Transient vasoconstriction : immediate vascular response irrespective

of the type of injury, mainly arterioles – Mild injury - 3-5 seconds – Severe
injury - 5 minutes
2. Persistent progressive vasodilatation : mainly arterioles, others to a
lesser extent. – obvious within half an hour of injury – increased blood
volume in microvascular bed of the area – redness and warmth
Hemodynamic changes

3. Progressive vasodilatation elevate the local hydrostatic pressure –

transudation of fluid into the extracellular space – swelling– swelling.
4. Slowing or stasis increased concentration of red cells, and thus, raised blood
viscosity.
5. Leucocytic Margination - peripheral orientation of leucocytes (mainly
neutrophils) along the vascular endothelium – stick to the vascular endothelium
briefly – move and migrate through the gaps between the endothelial cells -
extravascular space – This is known is emigration.
2. Altered Vascular Permeability

 Accumulation of edema fluid - interstitial compartment which comes from

blood plasma by its escape through the endothelial wall of peripheral
vascular bed.
 Escape of fluid is due to vasodilatation and consequent elevation in
hydrostatic pressure - transudate.
 Subsequently, the characteristic inflammatory edema, appears by
increased vascular permeability of microcirculation – exudate.
MECHANISMS OF INCREASED VASCULAR
PERMEABILITY
I. Contraction of endothelial cells.
II. Retraction of endothelial cells.
III. Direct injury to endothelial cells.
IV. Endothelial injury mediated by leucocytes.
V. Leakiness and neo-vascularization.
I. Contraction of endothelial cells.
• Contraction of endothelial cells
• Affects venules exclusively.
• Endothelial cells develop temporary gaps
• Contraction resulting in vascular leakiness
• Mediated by the release of histamine, bradykinin and other chemical
mediators
• Short duration (15-30 minutes) - immediately after injury.
II. Retraction of endothelial cells
• Retraction of endothelial cells
• Structural re-organisation of the cytoskeleton of endothelial cells
• Reversible retraction at the intercellular retraction at the intercellular
junctions.
• Mediated by cytokines such as interleukin-1 (IL-1) and tumour necrosis
factor (TNF)-α.
III. Direct injury to endothelial cells
• Causes cell necrosis and appearance of physical gaps.
• Process of thrombosis is initiated at the site of damaged endothelial cells.
• Affects all levels of microvasculature.
• Either appear immediately after injury and last for several hours or days –
severe bacterial infections.
• Or delay of 2-12 hours and last for hours or days - moderate thermal injury
and radiation injury
IV. Endothelial injury mediated by
leucocytes
• Adherence of leucocytes to the endothelium at the site of inflammation.
• Activation of leucocytes - release proteolytic enzymes and toxic oxygen.
• Cause endothelial injury and increased vascular leakiness.
• Affects mostly venules and is a late response.
V. Leakiness and neo-vascularization

• Newly formed capillaries under the influence of vascular endothelial

growth factor (VEGF).
• Process of repair and in tumors are excessively leaky.
B. CELLULAR EVENTS

• Cellular phase of inflammation consists of 2 processes

i. Exudation of leucocytes.
ii. Phagocytosis.
1. Exudation of leucocytes

1. Changes in the formed elements of blood.

2. Rolling and adhesion
3. Emigration
4. Chemotaxis
i. CHANGES IN THE FORMED ELEMENTS OF
BLOOD
• Central stream of cells comprised by leucocytes and RBCs and peripheral
cell free layer of plasma close to vessel wall.
• Later, central stream of cells widens and peripheral plasma zone becomes
narrower because of loss of plasma by exudation.
• This phenomenon is known as margination.
• Neutrophils of the central column come close to the vessel wall –
pavement.
ii. ROLLING AND ADHESION
• Peripherally marginated and pavemented neutrophils slowly roll over the
endothelial cells lining the vessel wall (rolling phase).
• Transient bond between the leucocytes and endothelial cellsleucocytes and
endothelial cells becoming firmer (adhesion phase).
• The following molecules bring about rolling and adhesion phases
• – Selectins – Integrins – Immunoglobulin gene superfamily adhesion
molecule
 iii. EMIGRATION
• After sticking of neutrophils to endothelium,
• The former move along the endothelial surface till a suitable site between the
endothelial cells is found endothelial cells is found where the neutrophils throw
out cytoplasmic pseudopods.
• Cross the basement membrane by damaging it locally – collagenases and escape
out into the extravascular space – emigration
• Diapedesis - escape of red cells through gaps between the endothelial cells –
passive phenomenon. – raised hydrostatic pressure haemorrhagic appearance to
the inflammatory– haemorrhagic appearance to the inflammatory exudate.
iv. CHEMOTAXIS
• After extravasating from the blood, Leukocytes migrate toward sites of
infection or injury along a chemical gradient by a process called chemotaxis.
• They have to cross several barriers - endothelium, basement membrane,
perivascular myofibroblasts and matrix.matrix.
• Potent chemotactic substances or chemokines for neutophils. – Leukotriene
B4 (LT-B4) - arachidonic acid metabolites. – Components of complement
system - C5a and C3a in particular. – Cytokines – Interleukins, in particular IL-
8.
EVENTS OF EXUDATION OF LEUCOCYTES
PHAGOCYTOSIS
• The process of engulfment of solid particulate material by the cells.
• 2 main types of phagocytic cells – Polymorphonuclear neutrophils
(PMNs) : early in acute inflammatory response, also known asacute
inflammatory response, also known as microphages – Macrophages :
Circulating monocytes and fixed tissue mononuclear phagocytes •
• This phagocytic cells releases proteolytic enzymes - lysozyme, protease,
collagenase, elastase, lipase, proteinase, gelatinase and acid hydrolases
PHAGOCYTOSIS

• The microbe undergoes the process of phagocytosis in following 3 steps :

– Recognition and attachment
– Engulfment Killing and degradation
– Killing and degradation
1. RECOGNITION AND ATTACHMENT
• Phagocytosis is initiated by the expression of surface receptors on
macrophages.
• Its further enhanced when the microorganisms are coated with specific
proteins, opsonins.
– Establish a bond between bacteria and the cell membrane of phagocytic cell. –
Major opsonins are
• IgG opsonin
• C3b opsonin
• Lectins
2. ENGULFMENT

• Formation of cytoplasmic pseudopods around the particle due to activation of

actin filaments around cell wall.
• Eventually plasma membrane gets lysed and fuses with nearby lysosomes –
phagolysosome.
3. KILLING AND DEGRADATION

• • Killing of MCO take place by Antibacterial substances further degraded by

hydrolytic enzymes
• • Sometimes this process fails to kill and degrade some bacteria like tubercle
bacilli.
OUTCOMES OF ACUTE INFLAMMATION
1. resolution - restoration to normal, limited injury – chemical substances
neutralization – normalization of vasc. permeability – apoptosis of
inflammatory cells – lymphatic drainage
2. healing by scar – tissue destruction – fibrinous inflammtion – purulent
inflammation & abscess formation (pus, pyogenic membrane, resorption -
pseudoxanthoma cells - weeks to months)
3. progression into chronic inflammation
INFLAMMATORY MEDIATORS
LOCAL MANIFESTATIONS

• Although all acute inflammatory reactions are characterized by vascular

changes and leukocyte infiltration, the severity of the reaction, its specific
cause, and the site of involvement introduce variations in its manifestations
and clinical correlates. These manifestations can range from swelling and the
formation of exudates to abscess formation or ulceration.
 EXUDATES
• Serous exudates are watery fluids low in protein content that result from plasma entering the
inflammatory site.
• Hemorrhagic exudates occur when there is severe tissue injury that damages blood vessels or
when there is significant leakage of red cells from the capillaries.
• Fibrinous exudates contain large amounts of fibrinogen and form a thick and sticky meshwork,
much like the fibers of a blood clot.
• Membranous or pseudomembranous exudates develop on mucous membrane surfaces and
are composed of necrotic cells enmeshed in a fibro purulent exudate.
• A purulent or suppurative exudate contains pus, which is composed of degraded white blood
cells, proteins, and tissue debris. Certain microorganisms, such as Staphylococcus, are more
likely to induce localized suppurative inflammation than others. An abscess is a localized area
of inflammation containing a purulent exudate that may be surrounded by a neutrophil layer
EXUDATE AND TRANSUDATE
CHRONIC INFLAMMATORY RESPONSE

• infiltration
• macrophages
• lymphocytes
• fibroblasts
• Leading to:
• persistent inflammation
• fibroblast proliferation
• scar formation
CHRONIC INFLAMMATION

• In contrast to acute inflammation, which is usually self-limited and of short

duration, chronic inflammation is self-perpetuating and may last for weeks,
months, or even years. It may develop as the result of a recurrent or
progressive acute inflammatory process or from low-grade, smoldering
responses that fail to evoke an acute response. Characteristic of chronic
inflammation is an infiltration by mononuclear cells (macrophages) and
lymphocytes instead of the influx of neutrophils commonly seen in acute
inflammation.
• Chronic inflammation also involves the proliferation of
fibroblasts instead of exudates. As a result, the risk of scarring
and deformity usually is greater than in acute inflammation.
• Agents that evoke chronic inflammation typically are low-grade,
persistent infections or irritants that are unable to penetrate
deeply or spread rapidly. Among the causes of chronic
inflammation are foreign bodies such as talc, silica, asbestos, and
surgical suture materials.
1. NONSPECIFIC CHRONIC
INFLAMMATION
• Nonspecific chronic inflammation involves a diffuse accumulation of
macrophages and lymphocytes at the site of injury.
• Ongoing chemotaxis causes macrophages to infiltrate the inflamed site, where
they accumulate owing to prolonged survival and immobilization.
• These mechanisms lead to fibroblast proliferation, with subsequent scar
formation that in many cases replaces the normal connective tissue or the
functional parenchymal tissues of the involved structures.
• For example, scar tissue resulting from chronic inflammation of the bowel causes
narrowing of the bowel lumen.
2. GRANULOMATOUS INFLAMMATION
• A granulomatous lesion is a distinctive form of chronic inflammation.
• A granuloma typically is a small, 1- to 2-mm lesion in which there is a massing of
macrophages surrounded by lymphocytes. These modified macrophages resemble
epithelial cells and sometimes are called epithelioid cells.
• Like other macrophages, the epithelioid cells are derived originally from blood
monocytes.
• Granulomatous inflammation is associated with foreign bodies such as splinters,
sutures, silica, and asbestos and with microorganisms that cause tuberculosis,
syphilis, deep fungal infections.
• A dense membrane of connective tissue eventually encapsulates the lesion and
isolates it. These cells are often referred to as foreign body giant cells.
SYSTEMIC MANIFESTATIONS OF
INFLAMMATION

1. Acute phase response

2. White Blood Cell response
3. Lymphadenitis