Inflammation

Rognidan Paper-1, Part A,

Section III, Point no 03
 Inflammation

• Definition –
“Inflammation is defined as the local response of living mammalian
tissue to injury due to any injurious agent”.

• Inflammation (word) – The act or an instance (example) of inflaming

– inflame i.e. burning.
 Causes of inflammation

1. Physical agents – like heat, cold, radiation, mechanical trauma.

2. Chemical agents – organic & inorganic poisons (usually of mineral origin).
3. Infective agents – bacteria, viruses, & their toxins.
4. Immunological agents – cell mediated & antigen-antibody reaction.
 Signs of Inflammation

• Rubor (redness)
• Tumor (swelling)
• Calor (heat)
• Dolor (pain).
• Functio laesa (loss of
function) was later added
by Virchow.
 Types of Inflammation

Acute Inflammation Chronic Inflammation

• Short duration & early body • Longer duration & delayed body
response. response.
• Resolves quickly & usually followed • Persists for a long time.
by healing. • Characteristic features are –
• Characteristic features are – • Formation of granulation tissue.
• Accumulation of fluid and • Presence of Lymphocytes &
plasma. plasma cells, macrophages as
• Presence of platelets & inflammatory cells.
neutrophils as inflammatory
cells.
 Acute Inflammation

• Vascular Events.
• Cellular Events.

• Vascular Events –
1. Haemodynamic changes.
2. Changes in vascular permeability.
 Haemodynamic changes
Transient Vasoconstriction of arterioles . Immediate response.

Mainly arterioles, increased blood

Persistent progressive Vasodilatation . volume – redness & warmth.

Elevation of Local Hydrostatic pressure. Transudation of fluid – swelling.

Increased permeability of
Slowing or Stasis. microvasculature & increased
viscosity of blood.
Leucocytes stick to Vascular
Leucocytic Margination – Emigration. endothelium, then move outside
into extravascular spaces.
Lewis Experiment
 Changes in Vascular permeability

• Pathogenesis – In and around the inflamed tissue, there is

accumulation of oedema fluid in the interstitial compartment which
comes from blood plasma by its escape through the endothelial wall
of peripheral vascular bed.
Primarily transudate is present. Afterwards as endothelial
permeability increases there is escape of intravascular cells which
leads to exudate formation.
 Difference Between Transudate & Exudate.

Transudate Exudate
• Due to Vasodilation & increased • Due to increased vascular
hydrostatic pressure. permeability of microcirculation.
• More protein content, • Low protein content.
• Specific gravity low. • Specific gravity high.
• Few cells, mainly mesothelial • Many cells, Inflammatory as well
cells & cellular debris. as parenchymal cells.
• E.g. Oedema in congestive • E.g. Purulent exudate( pus.)
 Starlings Hypothesis
• Normal circumstances – fluid balance is done by
two opposite forces.
1. Forces that causes outward movement of fluid.
2. Forces that cause Inward movement of fluid.
• In case of inflammatory conditions –
• Increased permeability of microvascular wall.
• That leads to decrease in intravascular osmotic
pressure & increase in extravascular osmotic
pressure.
• Ultimately resulting excessive outflow of fluid
from intravascular to extravascular which is
called as Exudate.
 Various Mechanisms of Increased Vascular permeability

1. Contraction of endothelial cells –

• Commonly affects venules
• Contraction of endothelial cells
• Formation of temporary gaps between
endothelium
• Mediated by hystamine, bradykinin
• Response begins immediately & usually
reversible
• Duration – short (15-30mins)
• E.g. Immediate transient leakage in mild
thermal injury of skin of forearm.
2. Retraction of endothelial cells –
• Structural reorganization of endothelial cells
causing retraction.
• Causes increase in gap between endothelial cells.
• Affects commonly venules.
• Mediated by cytokinase (Interleukin 1) & tumour
necrosis factor (TNF).
• Onset – 4-6 hrs.
• Duration – 2-4 hrs.

3. Direct injury to endothelial cells –

• Direct injury leading to necrosis & detachment of
that endothelial cell.
• Causing appearance of physical gap & triggers
thrombosis.
• Affects venules, capillaries, arterioles.
• 2 types
1. Immediate sustained leakage
2. Delayed prolonged leakage.
4. Endothelial injury mediated by leucocytes –
• Adherence of leucocytes to endothelium at site of
inflammation.
• Release of proteolytic enzymes Leadxic oxygen
species by adhered leucocytes.
• Causing endothelial injury.
• Ultimately resulting increased vascular leakiness
• Affects venules, capillaries
• Delayed prolonged response.

5. Leakiness in neovascularisation –
• Newly formed capillaries are excessively leaky.
 Cellular Events

1. Exudation of leucocytes
2. Phagocytosis.
 Exudation of leucocytes

• The escape of leucocytes from the lumen of microvasculature to the

interstitial tissue is the most important feature of inflammatory
response.
• Neutrophils, Monocytes & macrophages.
• Steps in migration of leucocytes are –
1. Changes in formed elements of blood.
2. Rolling & Adhesion.
3. Emigration
4. Chemotaxis.
Changes in the formed
elements of blood.
• In early stage rate of blood flow is
increased due to Vasodilatation.
Afterwards slowing or Stasis of
bloodstream takes place, this results in
change in normal axial flow of blood in
the microcirculation.
• Margination – due to slowing & stasis,
the central stream of cells widens &
peripheral plasma zone becomes
narrower because loss of plasma.
• Pavementing – As a result of this
redistribution, the neutrophils of the
central column come close to the
vessel wall.
 Rolling & Adhesion

• Rolling phase – Pavemented neutrophils slowly roll over the endothelial cells
lining the vessel wall.
• Adhesion phase – after rolling a transient bond between the leucocyte and
endothelial cell is formed.
• Adhesion molecules –
1. Selectins – P-Selectins, E-Selectins & L-Selectins.
2. Integrins.
3. Immunoglobulin superfamily adhesion molecules.
 Emigration
• After adhesion neutrophil move along endothelial surface till suitable
site is found, where neutrophils through out cytoplasmic pseudopods.
• Lodging of neutrophils inbetween endothelial cells and basement
membrane.
• Secretion of collagenases by neutrophil damages the basement
membrane and finally neutrophil escape out into extravascular space.
• Property of squeezing and throwing out pseudopods to escape
through gaps between endothelium is called as Diapedesis and the
process is called as Emigration .
 Chemotaxis

• The chemotactic factors mediated transmigration of leucocytes after

emigration to reach the Site of inflammation is called as Chemotaxis.
• Chemotactic substances – Chemokines
e.g. – Leukotriene B4 (LT-B4)
Platelet factor 4 (PF4)
Cytokines (Interleukins I,V,VI)
• In most forms of acute inflammation neutrophils predominate in the
inflammatory infiltrate during the first 6 to 24 hours and are replaced by
monocytes in 24 to 48 hours.
• In certain infections—for example, those produced by Pseudomonas
bacteria—the cellular infiltrate is dominated by continuously recruited
neutrophils for several days; in viral infections, lymphocytes may be the
first cells to arrive; in some hypersensitivity reactions, eosinophils may
be the main cell type.
• Once leukocytes (neutrophils and monocytes) have been recruited to a
site of infection or cell death, they must be activated to perform their
functions.
• The responses of leukocytes consist of two sequential sets of events: (1)
Recognition of the offending agents, which deliver signals that (2)
Activate the leukocytes to ingest and destroy the offending agents and
amplify the inflammatory reaction.
 Recognition of Microbes and Dead Tissues

1. Receptors for microbial products – Toll-like receptors (TLRs)

2. G protein–coupled receptors
3. Receptors for opsonins
4. Receptors for cytokines
 Removal of the Offending Agents

• The functional responses that are most important for destruction of

microbes and other offenders are phagocytosis and intracellular killing.
• Phagocytosis – Phagocytosis is defined as the process of engulfment of
solid particulate material by the cells (cell-eating). The cells performing this
function are called phagocytes. There are 2 main types of phagocytic cells
– 1. Neutrophils & 2.Macrophages.
• Phagocytosis involves three sequential steps –
1. Recognition and attachment of the particle to be ingested by the
leukocyte.
2. its Engulfment, with subsequent formation of a phagocytic vacuole.
3. killing or degradation of the ingested material.
1. Recognition and attachment
• mannose receptor and scavenger receptor.
• Opsonin & Opsonisation.
2. Engulfment
• Extensions of the cytoplasm (pseudopods & Pinching off plasma
membrane to form vesicle (phagosome) .
• The phagosome then fuses with a lysosomal granule, resulting in
discharge of the granule’s contents into the phagolysosome.
3. Killing or Degradation
• Oxygen Radicals.
• Nitric Oxide.
• Anti-Microbial Proteins.
• Anti-Microbial Peptides.
• Binding Proteins.
• Hydrogen Ion Transport.
• Other functional response of activated leucocytes
• Produce a number of growth factors, which contributes in process of tissue
repair after cell injury.
• Release of Leukocyte Products and Leukocyte-Mediated Tissue Injury -
“collateral damage.”
• Autoimmune diseases.
• Allergic diseases.

• Regulation of inflammation –
• 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.
• Neutrophils also have short half-lives in tissues and die by apoptosis within a
few hours after leaving the blood.
• Stop signals that serve to actively terminate the reaction.
 Mediators of inflammation
1. Cell-derived Mediators –
• Vasoactive Amines – histamine, serotonin, neuropeptide
• Arachidonic Acid (AA) Metabolites – prostaglandin, Thromboxane A2,
Prostacyclin, 5HETE, Leukotriene.
• Lysosomal compounds
• Platelet Aggrevating Factors
• Cytokines – IL1, IL6, IL8, IL12, IL17, TNF, Interferon,
• Free radicals oxygen metabolites & nitric oxide
2. Plasma Protein-derived Mediators (Plasma Proteases) –
• Kinin System - bradykinin
• Clotting System – fibrinopeptides
• Fibrinolytic System – plasmin
• Complement System –
 Vasoactive Amines
• Histamine – richest sources of histamine are the mast cells. also found in blood
basophils and platelets.
It is released by mast cell degranulation in response to a variety of stimuli, including
–
• heat, cold, irradiation, trauma, irritant chemicals, immunologic reactions
• Anaphylatoxins
• Histamine-releasing factors from neutrophils, monocytes and platelets.
• Cytokines – Interleukins.
Actions of histamine –
• Vasodilatation, increased vascular (venular) permeability, itching and pain.

• 5Hydroxytryptamine (5HT or serotonin) – It is present in tissues like

chromaffin cells of GIT, spleen, nervous tissue, mast cells and platelets. The actions of
5-HT are similar to histamine but it is a less potent mediator of increased vascular
permeability and vasodilatation than histamine.
• Neuropeptides – substance P, neurokinin A, vasoactive intestinal polypeptide
(VIP) and somatostatin. Actions of these neuropeptides are –
• Increased vascular permeability.
• Transmission of pain stimuli.
• Mast cell degranulation
 Arachidonic Acid (AA) Metabolites
• Metabolites via cyclo-oxygenase pathway
1. Prostaglandins – PGD2 and PGE2 act on blood vessels and cause increased
venular permeability, vasodilatation and bronchodilatation ultimately
causing oedema. PGF2-a induces vasodilatation and bronchoconstriction.
2. Thromboxane A2 - TxA2, a potent platelet-aggregating agent and
vasoconstrictor, broncho constrictior.
3. Prostacyclin (PGI2). – PGI2 induces vasodilatation, broncho dilatation and
inhibits platelet aggregation.

• Metabolites via lipo-oxygenase pathway

1. 5-HETE – potent chemotactic agent for neutrophils.
2. Leukotriene – smooth muscle contraction and thereby induce vaso-
constriction, broncho-constriction and increased vascular permeability.
 Lysosomal Compounds

• Granules of neutrophils Neutrophils have 3 types of granules:

primary or azurophil, secondary or speci fic, and tertiary.
• Granules of monocytes and tissue macrophages.
 Platelet Aggrevating Factor

• It is released from IgE-sensitised basophils or mast cells, other

leucocytes, endothelium and platelets. Actions of PAF are –
• Platelet aggregation.
• Increased vascular permeability
• Vasodilatation in low concentration and vasoconstriction
otherwise
• Bronchoconstriction
• Adhesion of leucocytes to endothelium
• Chemotaxis
 Cytokines

• Cytokines are polypeptide substances produced by activated

lymphocytes (lymphokines) and activated monocytes (monokines).
• The term chemokine is used for a family of substances which act as
chemoattractants for inflammatory cells.
• All these agents may act on ‘self’ cells which produced them or on
other cells.
Free radicals oxygen metabolites & nitric oxide

• Oxygen-derived metabolites are released from activated neutrophils and

macrophages and include superoxide oxygen (O’2), H2O2, OH’ products.
• Endothelial cell damage and thereby increased vascular permeability.
• Activation of protease and inactivation of anti pro tease causing tissue matrix
damage.
• Damage to other cells.
• Nitric oxide (NO)
• Vasodilatation.
• Anti-platelet activating agent.
• Possibly microbicidal action.
 Plasma Protein-derived Mediators.
• These include various products derived from activa tion and interaction of 4 interlinked
systems: kinin, clotting, fibrinolytic and complement.
1. Kinin System – This system on activation by factor Xlla generates bradykinin, so
named because of the slow contraction of smooth muscle induced by it. It acts in the
early stage of inflammation
• smooth muscle contraction
• vasodilatation
• increased vascular permeability
• pain.
2. Clotting System – Factor Xlla initiates the cascade of the clotting system resulting in
formation of fibrinogen which is acted upon by thrombin to form fibrin and
fibrinopeptides. Actions of fibrinopeptides
• increased vascular permeability
• chemotaxis for leucocyte
• Inhibits anticoagulant activity.
3. Fibrinolytic System – Formation of Plasmin
• Activation of haghman factor (XII) which stimulates the kinin system to
generate bradykinin.
• Activates complement protein C3 to C3a, which increases permeability.
• Degrades fibrin, which leads to increased permeability & chemotactic to
leucocytes.
4. Complement system – activation can occur by classical or alternate pathway.
Which give rise to anaphylatoxins (C3a, C4a, C5a) & Membrane attack complex
(C5b, C6, C7, C8, C9).
• C3a, C4a, C5a activates mast cells – release of histamine – increased vascular
permeability – oedema – augments phygocytosis.
• C5b, C6, C7, C8, C9 which causes holes in phospholipid Membrane.
 Inflammatory cells
1. Neutrophils –
• Initial phagocytosis – adhesion, emigration, chemotaxis, Engulfment.
• Engulfment of microbial material.
• Basement membrane damage.

2. Eosinophils – inflammatory response in following conditions

• Allergic conditions
• Parasitic infestation.
• Skin diseases
• Certain malignant lymphomas
3. Basophil & Mast cells –
• In immediate & delayed type of hypersensitivity reactions.
• Release of histamine by IgE sensitised basophils

4. Lymphocytes –
• Dominant in chronic inflammation & late stage of acute inflammation.
• Increased number in chronic inflammation e.g. Tuberculosis.

5. Plasma cells – antibody Synthesis.

• Active in prolonged infection with immunological response e.g. Syphilis, RA,
TB.
• Hypersensitivity states.
• Multiple myeloma.
6. Macrophages –
• Phagocytosis & pinocytosis.
• Produces variety of biological active substances –
• Proteases – collagenase & elastase.
• Plasminogen activator – activates fibrinolytic System
• Products of complement
• Coagulation factors
• Chemotactic agents
• Metabolites of Arachidonic acid.
• Growth promoter factors
• Cytokines
• Free radicals.
7. Giant cells – A few examples of multinucleate giant cells exist in normal
tissues (e.g. osteoclasts in the bones, trophoblasts in placenta, megakaryocytes in
the bone marrow). However, in chronic inflammation when the macro phages fail
to deal with particles to be removed, they fuse together and form multinucleated
giant cells. Besides, morphologically distinct giant cells appear in some tumours
also.
Giants cells in inflammation –
• Foreign body giant cells
• Langhans’ giant cells.
• Touton giant cells.
• Aschoff giant cells.
Giant cells in tumours –
• Anaplastic cancer giant cells –
• Reed Sternberg cells
• Osteoclastic giant cells of bone tumor.
Factors determining the inflammatory response
• Factors involving organisms –
1. Type of injury & infection.
2. Virulence.
3. Dose.
4. Portal of entry.
5. Product of organisms
• Factors involving hosts –
1. Systemic diseases.
2. Immune status of host.
3. Congenital neutrophil defects.
4. Leukopenia
5. Site or type of tissue involved.
6. Local host factors
Morphological variation of acute inflammation
• Variations according to type of Exudate –
1. Serous – Exudate resembles serum.
2. Fibrinous – fibrin content is high.
3. Purulent – caused by pyogenic bacteria.
4. Haemorrhagic – vascular damage
5. Catarrhal – surface inflammation of epithelium.
• Pseudomembranous inflammation –
• Ulcers
• Suppuration abscess formation
• Cellulitis
• Bacterial infections of blood –
1. Bacteraemia
2. Septicemia
3. Pyaemia
 Systemic effects of Acute inflammation

• Fever
• Leucocytosis
• Lymphangitis & lymphadenitis.
• Shock
 Fate of Acute inflammation

• Resolution
• Healing
• Suppuration
• Chronic inflammation.