• History

• Definition

• Agents causing inflammation

• Signs of inflammation

• Inflammatory cells

• Types of inflammation

• Acute inflammation

-Vascular event- 1) Haemodynamic changes

2) vascular permeability

• Mechanism of increased permeability

-Cellular event :-1) Exudation of leucocytes

2) Phagocytosis

Chemical Mediators of active inflammation.

• Chronic inflammation

• References

History:

• Egyptian Papyrus (3000 BC) -clinical features of inflammation. Celsus – cardinal signs of
inflammation.

• Virchow (1793)- added fifth sign.i.e loss of function

• Elie Metchnikoff – Phagocytosis.

• Sir Thomas Lewis – chemical substances such as histamine locally induced by injury mediate the
vascular changes of inflammation.

• Definition

• Inflammation is a complex reaction to injurious agent such as microbes and damaged necrotic
cells, that consists of vascular responses, migration and activation of leukocytes and systemic
reaction. (Robbins and Cotran 7th edition)

• Inflammation is defined as the local response of living mammalian tissues to injury due to any
agent.

• It is a body defense reaction in order to eliminate or limit the spread of injurious agent as well
as to remove the consequent necrosed cells and tissues.
 • Definition

• Inflammation is a complex reaction to injurious agent such as microbes and damaged necrotic
cells, that consists of vascular responses, migration and activation of leukocytes and systemic
reaction. (Robbins and Cotran 7th edition)

• Inflammation is defined as the local response of living mammalian tissues to injury due to any
agent.

• It is a body defense reaction in order to eliminate or limit the spread of injurious agent as well
as to remove the consequent necrosed cells and tissues.

• Signs of inflammation-

• Rubor (redness)

• Tumor (swelling)

• Dolor (pain)

• Functio laesa (loss of function)

• Calor (heat)

The inflammatory cells

1)Polymorphonuclear neutrophils(PMN)

-Also called as Neutrophils

-Neutrophils ,Basophils ,Eosinophils= Granulocytes.

-These granules contains substances like protease,

myeloperoxidase, lysozyme,estarase,cationic proteins etc.

MORPHOLOGY:

Size -Diameter of neutrophils ranges from 10-15µm .

Shape- They have multilobed nucleus,with 3 to 5 lobes joined by slender strands of genetic material.

-They are 40-70% of circulating leucocytes & there numbers increased in bacterial infection.

FUNCTIONS-

1) Phagocytosis -They form the 1st line of body defense in bacterial infection.

-The steps involved are adhesion of neutrophils to vascular endothelium, emigration through the vessel
wall, chemotaxis, engulfment, degranulation, killing, & degradation of foreign material.

2) Engulfment - of antigen-antibody complexes & nonmicrobial material

2)Eosinophils –

MORPHOLOGY

Size -They are larger than neutrophils about 12-17 micrometers in size.

Shape- They have two lobes to their nucleus. They stain bright red or reddish purple

-High level of steroid hormones leads to fall in number of eosinophils & even disappearance from blood.

-The number of eosinophils is increased in

1] Allergic condition.

2] Skin diseases.

3] Certain malignant lymphomas

3)Basophils – (Mast cells)

MORPHOLOGY

Size- They are 14-16 micrometers in diameter.

Shape- They are usually round.They have a multilobed nucleus.

- It is 1% of circulating leukocytes.

-Contains basophilic granules in cytoplasm, granules laden with heparin

& histamine.

*FUNCTION- Role in inflammation:-

1] Immediate and delayed type of hypersensitivity reaction.

2] Release of histamine.

4)Lymphocytes –

MORPHOLOGY

Size-They are 6-9 micrometer in diameter.

Shape- They appear amoeoid. They look alike monocytes except lymphocytes do not have kidney bean
shaped nucleus and lymphocytes are usually smaller.

-They are 20-45% of circulating lymphocytes.

-They are present in spleen,thymus,lymph node.

-Besides their role in antibody formation ( B-lymphocytes )& in cell-mediated

Immunity (T lymphocytes).
*FUNCTION-Number increased in chronic infections like tuberculosis.

5)Plasma cells –

MORPHOLOGY

Size- Larger than lymphocytes about 14-20 micrometer in diameter.

Shape- They are round to ovoid cells, having eccentrically placed nucleuswith chromatin arranged in
clock face (Art wheel).

-Plasma cells are normally not seen in peripheral blood.

-They develop from lymphocytes & rich in RNA & ˠ-globulin in cytoplasm.

-Their number is increased in-

1]prolonged infection with immunological response.

e.g Syphilis, tuberculosis

2]hypersensitivity states.

3] Multiple myeloma.

TYPES OF INFLAMMATION

Acute inflammation

Chronic inflammation

ACUTE INFLAMMATION

• Acute inflammation is a short duration & represents the early body reaction & is usually
followed by repair.

• Main features of acute inflammation are-

1] Accumulation of fluid & plasma at the affected site.

2] Intravascular activation of platelets and

3] Polymorphonuclear neutrophils as inflammatory cells

• Acute inflammation can be described under 2 headings-

• 1) Vascular events.

• 2) Cellular events.

VASCULAR EVENTS-

• Alteration in the microvasculature ( arterioles, capillaries, venules ) is the earliest response to

tissue injury.

• These alteration includes haemodynamic changes and changes in vascular permeability.

 • Alteration in the microvasculature ( arterioles, capillaries, venules ) is the earliest response to
tissue injury.

• These alteration includes haemodynamic changes and changes in vascular permeability.

• 1) Transient vasoconstriction of arterioles- With a mild form of injury, the blood flow may be
reestablished in 3-5sec. While with more severe injury the vasoconstriction may last for 5min.

• 2) Persistent progressive vasodilatation- Vasodilatation results in increased blood volume in

microvascular bed of the area, which is responsible for redness and warmth at the site of acute
inflammation.

• 3) Increase in local hydrostatic pressure - Progressive vasodilatation

• 4) Slowing or stasis.

Altered Vascular Permeability

• Pathogenesis :- In initial stage, the escape of fluid is due to vasodilation & consequent
elevation in hydrostatic pressure.

• This is transudate in nature.

• But subsequently, the characteristic inflammatory oedema, exudate, appears by increased

vascular permeability of microcirculation.

• In normal circumstances, the fluid balance is maintained by 2 opposing sets of forces-

1] Forces that causes outward movement of fluid from microcirculation are intravascular hydrostatic
pressure & osmotic pressure of interstitial fluid.

2] Forces that causes inward movement of interstitial fluid into circulation are intravascular osmotic
pressure & hydrostatic pressure of interstitial fluid.

• MECHANISM OF INCREASED VASCULAR PERMIABILITY-

-In acute inflammation, normally non-permeable endothelial layer of microvasculature becomes leaky.
 • Following mechanisms occurs

1] Contraction of endothelial cells

2] Retraction of endothelial cells

3] Direct injury to endothelial cells

4] Endothelial injury mediated by leucocytes

5] Neovascularisation

1] Contraction of endothelial cells-

-The endothelial cells develop temporary gaps between them due to their contraction resulting in
vascular leakiness.

-The response begins immediately after injury.

-Usually it is reversible & is for short duration (15-3 min).

2] Retraction of endothelial cells-

-Onset of response takes place 4-6 hours after injury & lasts for 24hrs or more.

-In this mechanism there is reorganisation of endothelial cells that causes reversible retraction at the
intercellular junction.

-This change affect venules & in mediated by cytokines such as interleukin-1 (IL-1) & tumor necrosis
factor.(TNF)

3]Direct injury to endothelial cells-

-It causes cell necrosis & appearance of physical gaps at the site of detached endothelial cells.

-Process of thrombosis is initiated at the site of damaged endothelial cells.

-Changes affects all levels of microvasculature (venules, capillaries, arterioles).

-The increased permeability may either appear immediately after injury & lasts for several hours or days.

4]Endothelial injury mediated by leucocytes-

-Adherence of leucocytes to the endothelium at the site of inflammation may results in

activation of leucocytes.

-The activated leucocytes release proteolytic enzymes & toxic oxygen species which may cause
endothelial injury & increased vascular leakiness.

-This form of increased vascular leakiness affects mostly venules & is late response.

5] Neovascularisation-
 -The newly formed capillaries under the influence of vascular endothelium growth factor (VEGF)
during the process of repair & in tumors are excessively leaky.

• Cellular events

• exudation of leucocytes

• Phagocytosis

a) Exudation of leucocytes

1]Changes in the formed elements of blood-

-In early stage of inflammation,the rate of flow of blood is increased due to vasodilatation.

-But subsequently, there is slowing/stasis of blood.

-With stasis change in normal axial flow of blood takes place.

-The normal axial flow consists of central stream of cells consist of leucocytes & RBC’s & peripheral
cell free layer of plasma close to vessel wall.

Due to slowing & stasis the central stream of cells widens & peripheral plasma zone becomes narrower
because of loss of plasma by exudation this is called as MARGINATION.

-As a result of this redistribution, the neutrophils of the central column come close to the vessel wall,
this is known as PAVEMENTING

2]Rolling and adhesion-

- Peripherally marginated & pavemented neutrophils slowly roll over the endothelial cells lining the
vessel wall (rolling phase).

-This is followed by the transient bond between the leucocytes & endothelial cells becoming firmer
( adhesion phase).

- The following adhesion molecules bring about rolling & adhesion phases-

3]Emigration-

-After sticking of neutrophils to endothelium, the former move along the endothelial surface .

-Till a suitable site between the endothelial cells is found where the neutrophils throw out cytoplasmic
pseudopods.

-Subsequently, the neutrophils lodges between the endothelial cells & basement membrane .

- It cross the basement membrane by damaging it locally with secreted collagenases & escape out into
the

extravascular space ; this is

 known as EMIGRATION.

The damaged basement membrane is repaired almost immediately.

- Simultaneous to emigration of leucocytes, escape of red cells through gaps between the endothelial
cells, DIAPEDESIS takes place.

-Diapedesis gives haemorrhagic appearance to the inflammatory exudate.

4] Chemotaxis-

-The chemotactic factor mediated transmigration of leucocytes after crossing several barriers
(endothelium, basement membrane, perivascular myofibroblast & matrix) to reach the interstitial
tissues is called as chemotaxis.

-The agents acting as potent chemotactic substances for different leucocytes called Chemokines are as
follows-

1] Leukotriene B4

2] Platelet factor 4

3] Cytokinase ( Interleukins IL-1,IL-5, IL-6)

4] Chemotactic factor for CD4+ T cells.

-In addition, chemotactic agents also induced leucocyte activation that includes –

the production of arachidonic acid metabolites, degranulation & secretion of lysosomal enzymes,
generation of oxygen metabolites.

PHAGOCYTOSIS

• It is defines as the process of engulfment of solid particulate material by the cells.

• Phagocytic cells :

1) Polymorphonuclear neutrophils (microphages).

2) Monocytes (macrophages).

Steps in Phagocytosis

1) Recognition and attachment stage (opsonisation)

2) Engulfment stage.

3) Secretion (degranulation stage).

4) Digestion (degradation stage).

1] RECOGNITION & ATTACHMENT STAGE-

-The phagocytic cells are recognised &attracted to bacteria by chemotactic factors released by bacterial
products as well as tissue protiens.
-To established bond between bacteria & the cell membrane of phagocytic cell, the micro-organism get
coated with opsonins.

- Which are naturally occuring factor in serum.

-The main opsonin present in the serum & their corresponding receptors on the surface of phagocytic
cells (PMNs or macrophages) .

a] IgG opsonin is the Fc fragment of immunoglobulin G, it is naturally occuring antibody in the serum
that coats the bacteria while the PMNs posses receptors for the same.

b] C3b opsonin is the fragment of complement; it is generated by activation of complement pathway.

-It is strongly chemotactic for attracting PMNs to bacteria.

c] LECTIN are carbohydrate binding proteins in the plasma which bind to bacterial cell wall.

2] ENGULFMENT STAGE-

- The opsonised particles bound to the surface of phagocytes is ready to be engulfed.

- This is formed by cytoplasmic pseudopods around the particles due to activation of actin
filaments beneath the cell wall, enveloping in the phagocytic vacuole.

- Eventually the plasma membrane enclosing the phagocytic vacuole breaks from the cell surface so
that membrane lined phagocytic vacule lies free in the cell cytoplasm.

- The lysosomes of cell fuses with the phagocytic vacuole & form phagolysosome or phagosome.

3] DEGRANULATION STAGE-

-During this process the preformed granule-stored products of PMNs are discharged or secreated into
the phagosomes & the extracellular environment .

-In particular, the specific or secondary granules of PMNs are discharged (e.g.lysosomes).

-Besides the discharge of preformed granules, mononuclear phagocytes synthesise & secrete certain
enzymes ( Interlukin 2& 6, TNF), arachidonic acid metabolites (e.g. prostaglandins, leukotrienes, platelet
activating factor) & oxygen metabolites (e.g. hydrogen peroxide, hypochlorous acid)

4] KILLING / DEGRADATION STAGE-

- Next comes the stage of killing & digestion of microorganism completing the role of phagocytes as a
scavanger cells.

-The micro organism after being killed by antibacterial substances are degraded by hydrolytic enzymes.

Chemical Mediators of Acute Inflammation-

1] CELL-DERIVED MEDIATORS-

1. Vasoactive amines (Histamine, 5-hydroxytryptamine)

2. Arachidonic acid metabolites (Eicosanoids)

 a] Metabolites via cyclo-oxygenase pathway.

b] Metabolites via lipo-oxygenase pathway.

3. Lysosomal components.

4. Platelet activating factor.

5. Cytokinase ( IL-1, TNF-ß ,Chemokinase)

2] PLASMA DERIVED MEDIATORS (plasma protease)- These are products of

1. The kinin system

2. The clotting system

3. The fibrinolytic system

4. The complement system

1] VASOACTIVE AMINE-

-Two importanat pharmacologically active amines that have role in early inflammatory response (first 1
hour) are histamine & 5-hydroxytryptamine (5-HT) or serotonin.

i] HISTAMINE-

-It is stored in granules of mast cell, basophils, platelets.

-Histamine are released from these cells by various agents as under-

a} Stimuli inducing acute inflammation

-E.g Heat,cold,trauma,irritant chemicals.

b}Interleukins.

c} Histamine releasing factors from neutrophils, monocytes, platelets.

-The main action of histamine are vasodilatation, pain, itching, increased vascular permiability
{venular}.

Ii] 5-Hydroxytryptamine (5-HT / Serotonin )

- It is present in tissue like spleen, chromaffin cells of GIT, nervous tissue, mast cells & platelets.

- The action of 5-HT are similar to histamine but it is less potent mediators of increased vascular
permiability & vasodilatation than histamine.

2] ARACHIDONIC ACID METABOLITES ( EICOSANOIDS )-

-Arachidonic acid is a fatty acid, & its main sources are

1]From diet directly,

2]Conversion of essential fatty acid, linoleic acid to arachidonic acid.

I ] Metabolite via cyclo-oxygenase pathway- (prostagliandin, thromboxane A2, prostacyclin):-

-Cyclo-oxygenase is a fatty acid enzyme which acts on activated arachidonic acid to form prostaglandin
endoperoxide (PGG2).

-PGG2 is enzymatically transformed into PGH2 with generation of free radical of oxygen.

-PGH2 is further acted upon by

enzymes & results into formation

of following 3 metabolites-

a] Prostaglandins ( PGD2, PGE2,

PGF2-alfa )

b] Thromboxane A2 (TXA2)

c] Prostacyclin (PGI2)

i] Metabolites via lipo-oxygenase pathway-

-The enzyme lipo-oxygenase acts on activated arachidonic acid to form hydroxyperoxy compound, 5-
HPETE (hydroperoxy eico-satetraenoic acid) which on further peroxidation forms the following 2
metabolites-

A] 5-HETE ( hydroxy compound) which is potent chemotactic agent for neutrophils.

B] Leukotrienes (LT) or slow reacting substance of anaphylaxix ( SRS-As) are so named as they are first
isolated from leucocytes.

-Firstly unstable leucocytes A4 (LTA4)

Is formed which acted upon enzymes

to form LTB4 (chemotactic for -

phagocytic cells & stimulates

Phagocytic cell adherence).

-While LTC4, LTD4, LTE4 have common

action.

3] LYSOSOMAL COMPONENTS –

-The inflammatory cells neutrophils & monocytes, contains lysosomal granules which on release
elaborate variety of mediators of inflammation. These are under:-

a] Granules of neutrophils-

b] Granules of monocytes & tissue macrophages.

A] Granules of neutrophils-

- These are of 2 types azurophil/primary & specific/secondary.

-Azurophil granules have myeloperoxidase, acid hydrolases.

-Specific granules contains lactoferrin, lysozyme,alkalline phosphatase & collagenase.

B] Granules of monocytes & tissue macrophages-

- These cells on degranulation release mediators of inflammation like acid proteases, collagenase,
elastase.

-However they are more active in chronic inflammation than acute inflammation.

4] PLATELET ACTIVATING FACTORS (PAF)-

-It is released from IgE-sensitised basophils or mast cells, other leucocytes, endothelium & platelets.

-Action of PAF are:-

a] Increased vascular permiability,

b] broncoconstriction,

c] chemotaxix,

d] adhesition of leucocyte to endothelium.

5] CYTOKINES (IL-1, TNF, Chemokinase)

- Cytokines are polypeptide substances produced by activated lymphocytes (lymphokines)

&activated monocytes (monokines).

-The action of various cytokines as mediator of inflammation are as under-

A] IL-1, TNF-a, TNF-ß :-

-Induced endothelial effects in the form of increased leucocyte adherence, thrombogenicity.

B] IF (interferon gamma) :– causes activation of macrophages & neutrophils & is associated with
synthesis of nitric acid synthase.

C] Chemokinase :- are a family of chemoattractant for inflammatory cells includes:-

i) IL-8 chemotactic for neutrophils;

ii) Platelet factor-4 chemotactic for neutrophils, monocytes, eosinophils.

6] NITRIC OXIDE & OXYGEN METABOLITES-

-Nitric oxide (NO) was originally described as vascular relaxation factor produced by endothelial cells.

-NO plays following role in inflammation:-

1] Vasodilation

2] Antiplatelet activating agent

3] Possibly microbicidal action

II] PLASMA DERIVED MEDIATORS (PLASMA PROTEASES)

-These includes the various products derived from activation & interaction of 4 interlinked systems:-
Kinin, Clotting, Fibrinolytic & Complement.

-Each of these system has its inhibitors & accelerator in plasma with negative & positive mechanisms
respectively.

- Hageman factor (XII ) of clotting system plays a key role in interaction of the four system.

1] THE KININ SYSTEM-

-This system on activation of by factor XIIa generate bradykinin,

so named because of slow contraction of smooth muscle it

induces.

-Kallikrein is formed from plasma prekallikrein by the action of

prekallikrein activator which is a fragment of factor XIIa.

-Kallikrein is then acts on high molecular weight kininogen to

form bradykinin.

2] THE CLOTTING SYSTEM

-Factor XIIa initiates the cascades of the clotting system resulting in

formation of fibrinogen which is acted upon by thrombin

to form fibrin & fibrinopeptides.

-The action of fibrinopeptides in inflammation are :-

a] Increased vascular permiability.

b] Vasodilation.

c] Anticoagulant activity.

d] Chemotaxis for leucocytes.

3] THE FIBRINOLYTIC SYSTEM

-This system is activated by plasminogen activator, the sources of which include kallikrein of the kinin
system, endothelial cells & leucocytes.

-Plasminogen activator acts on plasminogen present as component of plasma proteins to form plasmin.
-Further breakdown of fibrin by plasmin forms

fibrinopeptides or fibrin split products.

-The action of plasmin in inflammation are:-

a] activation of factor XII to form prekallikrein activator

that stimulates the kinin system to generate bradykinin,

b] Splits off complement C3 to form C3a which is a Permiability factor. &

c] Degrades fibrin to form fibrin split products which Increases vascular permiability & are chemotactic
to leucocytes

4] THE COMPLEMENT SYSTEM

-Activation of complement system can occurs either

a] by classic pathway through antigen-antibody complexes or

b] by alternate pathway via non-immunologic agents such as bacterial toxins, cobra venoms & IgA.

Chronic inflammation

-Chronic inflammation is defined as prolonged process in which tissue destruction and inflammation
occur at the same time.

-Characteristic feature of chronic inflammation is presence of chronic inflammatory cells such as

lymphocytes, plasma cells & macrophages.

TYPES OF CHRONIC INFLAMMATION-

-Chronic inflammation is subdivided into 2 types:-

A] Non-specific :- when the irritant substances produces a non-specific chronic inflammatory reaction
with formation of granulation tissue & healing by fibrosis.

e.g. Chronic ulcer, Chronic osteomyelitis.

B] Specific :- When the injurious agent causes a characteristic histologic tissue response.

e.g. tuberculosis , leprosy ,syphilis.

• Chronic inflammation can be caused by one of the following 3 ways-

1] Chronic inflammation following acute inflammation-

-When the tissue destruction is extensive, or the bacteria survive & persist in small number at the site
of acute inflammation. E.g. in Osteomyelities, Pneumonia, terminating in lung abscess.

2] Recurrent attacks of acute inflammation-

 -When repeated attacks of acute inflammation culminate in chronicity of the process. E.g. in recurrent
urinary tract infection leading to chronic pyelonephritits, repeated acute infection of gallbladder leading
to chronic cholecystitis.

3] Chronic inflammation starting de novo-

-When the infection with organisms of low pathogenicity is chronic from the beginning e.g. infection
with Mycobacterium tuberculosis.

Granulomatous Inflammation

It is a form of chronic inflammation characterized by collection of activated macrophages, often with T-

lymphocytes, & sometimes associated with central necrosis.

- Granuloma formation is a cellular attempt to contain an offending agent that is difficult to eradicate.

-Examples of diseases of granulomatous inflammation are:-

1] Tuberculosis :- Caused by mycobacterium tuberculosis- In this caseating granuloma (tubercle), focus

of activated macrophages (epithelioid cells), rimmed by fibroblast, lymphocytes, histiocytes, central ss

2] Crohn disease (inflammatory bowel disease) :- In this occasional noncaseating granulomas in the wall
of intestine, with dense chronic inflammatory infiltrate.

3] Leprosy:- In this acid-fast bacilli in macrophages; noncaseating granulomas occurs.

• SYSTEMIC EFFECTS OF CHRONIC INFLAMMATION-

1] FEVER-

• Invariably there is mild fever, often with loss of weight & weakness.

2] ANAEMIA-

• Chronic inflammation may shows anemia of varying degree.

3] LEUCOCYTOSIS-

• As in acute inflammation, chronic inflammation also has leucocytosis but generally there is
relative lymphocytosis in these cases.

References

• Robbins and Cotran -pathologic basis of diseases(7 th edition)

• Harsh Mohan – pathology(5th edition)