INFLAMMATION PATHOPHYSIOLOGY

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DAWN V TOMY M.Pharm.,Asst.Professor,Dept. ofPharmacology, ST.JOSEPH’S COLLEGEOFPHARMACY,CHERTHALA.
INFLAMMATION-burning
INFLAMMATION: It is the body’s local protective defense response to eliminate or limit
spread of injurious agents and removal of consequent necrosis.
AGENTS CAUSING INFLAMMATION:
1. PHYSICAL - heat burns, cold frost bite, radiation, mechanical trauma.
2. CHEMICAL - organic/inorganic poisons.
3. INFECTIVE - bacteria, fungi, virus etc...
4. IMMUNOLOGICAL – cell/antigen mediated.
5. TISSUE NECROSIS - ischemia.
THE 4 CARDINAL SIGNS BY CELSUS BY (ROMAN WRITER)
 RUBOR - Redness.
 TUMOR - Swelling.
 CALOR - Heat.
 DOLOR - Pain.
 Loss of Function- FUNCTIO LAESA.
CLASSIFICATION BASED ON: defense capacity of the host and duration of
inflammatory response.
TYPES:
1. ACUTE – of short duration (less than 2 weeks). Early body reaction to injury
followed by repair and healing.
FEATURES:-
a) Accumulation of fluid.
b) Intravascular activation of platelets.
c) Polymorph nuclear neutrophil as inflammatory cells.
2. CHRONIC – of long duration. After acute inflammation or stimulus induced chronic
inflammation.
FEATURES:-
Cells: lymphocytes, plasma cells, macrophages, granulation tissue formation.
3. SUBACUTE INFLAMMATION: - the type of inflammation in between the transition
from acute to chronic.

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EVENTS: - It is a continuous process consists of both vascular events and cellular events.
VASCULAR EVENTS
1. HAEMODYNAMIC CHANGES - changes in the vascular flow.
 Transient vasoconstriction – it is an immediate response in the arterioles and
blood-flow re-establishes in 3-5 seconds (mild) to 5 minutes (severe).
 Persistent progressive vasodilatation – it occurs mostly in arterioles and in
venules to less extent. Capillaries also dilate within half hour resulting in
increased blood volume in the microvascular bed and feeling of warmth and
redness at the site.
 Elevation of local hydrostatic pressure - vasodilatation cause increased local
hydrostatic pressure results in transudation of fluid into extra cellular space results
in swelling at the local site of acute inflammation.
 Slowing or stasis of microcirculation causes accumulation of RBCs and raises
blood viscosity.
 Leukocyte margination:
 Peripheral orientation of leukocytes (neutrophils) along the vascular
endothelium.
 Leukocytes stick to endothelial cells and then move and migrate to gaps of
endothelium to extravascular space known as emigration.
Triple response: flush, flare and wheal.
Features of triple response:
 Red line/Flush: due to local vasodilation of capillaries and venules.
 Flare: bright reddish appearance due to vasodilation of adjacent arterioles.
 Wheal: Swelling/edema of the surrounding skin due to transduction of fluid into
the extravascular space.
2. ALTERED VASCULAR PERMEABILITY - Vascular permeability is increased. Non
permeable endothelial layer become leakier. At initial stage there is accumulation of edema
fluid around inflamed tissue from plasma due to vasodilation and consequent elevation in
hydrostatic pressure.
 1st transudate – non inflammatory edema, less cells, less protein.
 Then exudate – inflammatory edema – more proteins, cells, pus etc.
 For balance of hydrostatic pressure and osmotic pressure as per starlings
hypothesis
 Endothelial cell contraction of venules – immediate transient response, post
capillary venules develop temporary gaps and vascular leakiness for short duration
and reversible within 15–30 minutes.
 Histamine, bradykinin, Leukotriene etc. are released.

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 Endothelial cell retraction – structural reorganization of cytoskeleton of
endothelial cells and causes reversible retraction of intercellular junctions of cells
4-6 hours - 24 hours Interleukins, TNF-alpha.
 Increased permeability immediately after injury and lasts for several hours/days
 Cell injury by leukocytes – venules and capillaries, leukocyte adherence and
activation – release mediators.
 Non permeable endothelial layer become leakier.
Direct injury to endothelial cells – cell necrosis, appearance of physical gaps, and initiate
process of thrombosis - all mediators affects arteries, capillaries and veins.
Neovascularization - VEGF stimulates angiogenesis - blood vessel remains leaky until
maturation of endothelial cells in case of repair and tumor.
FLUID: transudate and exudate
 Outward movement of fluid from microcirculation: Due to increased hydrostatic
pressure and decreased colloidal osmotic pressure of interstitial fluid.
 Inward movement of fluid into circulation: Due to increased intravascular
colloidal osmotic pressure and decreased hydrostatic pressure of interstitial fluid.
 Transudate: filtrate of blood plasma without changes in endothelial permeability.
Found in non-inflammatory edema. It contains mainly albumin and traces of
fibrinogen hence no tendency to coagulate along with few cells mainly
mesothelial cells and cellular debris. E.g. in Congestive cardiac failure.
 Exudate: Edema of inflamed tissue associated with increased vascular
permeability. Found in inflammatory edema. Readily coagulate due to high
content of fibrinogen and other coagulation factors with many cells mainly
inflammatory as well as parenchymal. E.g. PUS.

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CELLULAR EVENTS
I. EXUDATION OF LEUKOCYTES.
 Escape of leukocytes from blood vessel to interstitial space. The cells includes:
o Polymorphonuclear Neutrophils (PMN)
o Monocytes
o Macrophages
 This is the first line response in the case of acute inflammation.
1. Changes in formed elements of blood are due to stasis, margination and pavementing.
 Stasis – stoppage of flow of blood i.e. normal axial blood flow is disturbed.
 Margination i.e. central stream of blood cells widens and peripheral plasma zone
becomes narrower as plasma exudates (oozes out).
 Pavementing - neutrophils of central stream of blood cells comes close to vessel wall.
2. Rolling and adhesion
 Peripherally marginated and pavemented neutrophils roll over the membrane which
lines the walls of the blood vessels (endothelial cells).
 Adhesion occurs by transient bond formation between leukocytes and endothelial
cells by selectins, integrins and immunoglobulin super family adhesion molecules.
o Selectins.
 P selectins – preformed and stored in endothelial cells &
platelets.
 E selectins – from cytokine activated endothelial cells.
 L selectins – from lymphocytes and neutrophils.

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o Integrins.
 It activates receptors on endothelial cell wall and neutrophils, which
causes firm adhesion.
o Immunoglobulin super family adhesion molecule.
 ICAM 1 and 2 locates the neutrophils.
3. Emigration
 After sticking, neutrophils move along the cell, between endothelial cells of basement
membrane using pseudopods and damaging basement membrane by collagenase
through which, neutrophils cross basement membrane and escapes out to the extra
vascular space. Damaged basement membrane repaired immediately.
 For the 1st 24 hours of inflammation neutrophils are present at the site which then dies
out.
 For the next 24 - 48 hours monocytes and macrophages are present.
 Diapedsis: It is the escape of red blood cells through gaps in the endothelial cells. It is
a passive process and gives a haemorrhagic appearance to exudate.
4. Chemotaxis – chemical attraction.
 The chemotactic factors mediated trans-migration of leukocytes crossing several
barriers (endothelium, basement membrane, perivascular fibroblasts, and extracellular
matrix) to reach interstitial tissues.
 Chemotactic factors for neutrophils includes:
o Leukotriene.
o Cytokines.
o Soluble bacterial product.
o Component of complement system.
 Other mediators + chemokines - (LT-B4, PF4, complement system components (C3,
C5), cytokines (IL1, 5 & 6), soluble bacterial products, monocyte chemotactic protein,
chemokine for CD4T cells, eotaxin for eosinophils etc.).
II. PHAGOCYTOSIS
 Role of neutrophils in inflammation
 Cell eating, engulfing solid particles by cells named phagocytes
 Performed mainly by two phagocytic cell types - PMNs or called
microcytes/microphage.
 Circulating monocytes and fixed tissue monomolecular phagocytic macrophages.
 Neutrophils and macrophages on reaching tissue releases proteolytic enzymes
(lysozyme, gelatinase, acid hydrolase, protease, elastase, proteinases, collagenase and
lipase) which degrades collagen and extracellular matrix.
 Followed by phagocytosis by neutorphills.
 Occurs in 4 steps.

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1. Recognition and attachment
 Binding of opsonized particle to phagocytic cells.
 Surface receptors on macrophages (mannose and scavenger receptor) recognize
microorganisms and coat them with protein opsonin.
 Bacterial products also attract phagocytic cells and get coated with opsonins.
 Opsonins – establishes a bond between bacteria and cell membrane of phagocytic cell.
 Main opsonins includes:
o IgG opsonin – antibody.
o C
3b
opsonin – from complementary system.
 Lectins – Carbohydrate binding protein.
2. Engulfment stage
 Formation of cytoplasmic pseudopods around particles due to activation of actin
filaments beneath cell wall enveloping it in a phagocytic vacuole.
3. Degranulation stage
 Formation of phagocytic vacuole and granules both outside and inside of the cells.
 Enzymes kill and one or more lysosomal granules from PMN fused with vacuoles
form phagosome or phagolysosome. It breaks of plasma membrane enclosing cell
inclusions and they become free in cell cytoplasm.
4. Killing (by antibacterial substances) and degradation by hydrolytic enzymes.
 Mainly 3 ways.
A. O2 dependent bactericidal mechanism – reactive O2 species – O2
-, H2O2, OH- ,
HOCl, HOBr, HOI.
B. O2 independent bactericidal mechanism – lysosomal hydrolase, permeability
increasing factors, defensing, cationic proteases.
C. Nitric oxide mechanism – can kill, it is formed from endothelial cells activated by
macrophages.
 O2 - NADPH oxidases - 2O2.
 Myeloperoxidase dependent – HOCl.
 MPO independent – Haber weis reaction - OH- Fenton reaction Fe3+ - OH-.

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CHEMICAL MEDIATORS OF INFLAMMATION
Permeability factors or endogenous mediators of increased vascular permeability are large
number of endogenous compounds which enhances vascular permeability. Many chemical
mediators take part in processes of acute inflammation like vasodilatation, chemotaxis, fever,
pain and tissue damage.
Chemical mediators of inflammation are released from the cells, the plasma, or damaged
tissue.
They are classified into 2 groups:
1. Cell-derived Mediators; and
2. Plasma-derived Mediators (Plasma Proteases).

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I. CELL-DERIVED MEDIATORS
1. Vasoactive Amines: The important pharmacologically active amines in the early
inflammatory response (first one hour) are:
i. Histamine
ii. 5-hydroxytryptamine (5-HT) or serotonin and
iii. Recently added group of neuropeptides.
i. Histamine. It is stored in the granules of mast cells (it contains histamine, heparin,
immunoglobulin-E), basophils and platelets. Histamine is released from these cells by
various agents like:
a) Stimuli or substances inducing acute inflammation e.g.heat, cold, irradiation,
trauma, irritant chemicals, immunologic reactions etc.
b) Anaphylatoxins like fragments of complement C3a, and C5a, which increase
vascular permeability and cause oedema in tissues.
c) Histamine-releasing factors from neutrophils, monocytes and platelets.
d) Interleukins: They are lymphokines – polypeptides produced by activated
lymphocytes.
Actions of histamine:
a) Vasodilatation
b) Increased vascular (venular) permeability and
c) Itching and pain.
Stimulation of mast cells and basophils also releases products of arachidonic acid
metabolism. Releases slow reacting substances of anaphylaxis (SRS-As) which, consist of
various leukotrienes (LTC4, LTD4 and LTE4).

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ii. 5-Hydroxytryptamine (5-HT or serotonin). It is present in tissues like chromaffin
cells (affinity towards chromium salts) of GIT, spleen, nervous tissue, mast cells and
platelets.
Actions of 5-HT are similar to histamine but is less potent.
iii. Neuropeptides: Recently added vasoactive amines include tachykinin neuropeptides,
such as substance P, neurokinin-A, vasoactive intestinal polypeptide (VIP) and
somatostatin. These small peptides are produced in the central and peripheral nervous
systems.
Actions of neuropeptides:
a) Increased vascular permeability
b) Transmission of pain stimuli and
c) Mast cell degranulation.
2. Arachidonic Acid Metabolites (Eicosanoids 20 ‘C’ atoms): It is the most potent
mediators of inflammation. Arachidonic acid (a constituent of the phospholipid cell
membrane) is released by the enzyme phospholipases during cell damage. It is activated
to form arachidonic acid metabolites or eicosanoids by 2 pathways:
a) Cyclo-oxygenase pathway and
b) Lipo-oxygenase pathway.

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a) Metabolites via cyclo-oxygenase pathway:
i. Prostaglandins
ii. Thromboxane-A2
iii. Prostacyclin and
iv. Resolvins.
Prostaglandins and related compounds are also called autocoids. Cyclo-oxygenase (COX), a
fatty acid enzyme present as COX-1 and COX-2, 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 and results in
formation of 3 metabolites:
a). Prostaglandins (PGD2, PGE2 and PGF2-α):
PGD2 and PGE2 act on blood vessels to cause increased venular permeability,
vasodilatation and bronchodilatation and inhibit inflammatory cell function.
PGF2-α induces vasodilatation and bronchoconstriction.
b). Thromboxane A2 (TXA2):
Platelets contain the enzyme thromboxane synthetase.
TXA2 is active in platelet aggregation, vasoconstriction and bronchoconstriction.
c). Prostacyclin (PGI2):
PGI2 induces vasodilatation, Broncho-dilatation and inhibits platelet aggregation.
d). Resolvins:
These mediators act by inhibiting production of pro-inflammatory cytokines and are
helpful. Drugs like aspirin act by inhibiting COX activity and stimulating production
of resolvins.
The major anti-inflammatory drugs act by inhibiting activity of the enzyme COX; e.g. non-
steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors.

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b) Metabolites via lipo-oxygenase pathway: 5-HETE, leukotrienes and lipoxins. Lipo-
oxygenase is a predominant enzyme in neutrophils, acts on activated arachidonic acid to form
hydroperoxy eicosatetraenoic acid (5-HPETE) which on further peroxidation forms 2
metabolites:
a) 5-HETE (hydroxy compound), an intermediate product, is a potent chemotactic
agent for neutrophils.
b) Leukotrienes (LT): First isolated from leucocytes. Unstable leukotriene A4 (LTA4)
is acted upon by enzymes to form LTB4,which is chemotactic for phagocytic cells and
stimulates phagocytic cell adherence. LTC4, LTD4 and LTE4 have common actions
causing smooth muscle contraction, vasoconstriction, bronchoconstriction and
increased vascular permeability. They are also called as slow reacting substances of
anaphylaxis (SRS-As).
c) Lipoxins (LX) are recently described product of lipooxygenase pathway.
Lipooxygenase-12 present in platelets acts on LTA4 derived from neutrophils and
forms LXA4 and LXB4. Lipoxins regulate and counterbalance actions of leukotrienes.
3. LYSOSOMAL COMPONENTS. The inflammatory cells-neutrophils and monocytes,
contain lysosomal granules which release a variety of mediators of inflammation.
i) Granules of neutrophils. Neutrophils have 3 types of granules: primary or azurophil,
secondary or specific, and tertiary.
a) Primary or azurophil granules are large azurophil granules which contain functionally
active enzymes. These are myeloperoxidase, acid hydrolases, acid phosphatase, lysozyme,
defensin (cationic protein), phospholipase, cathepsin G, elastase, and protease.
b) Secondary or specific granules contain alkaline phosphatase, lactoferrin, gelatinase,
collagenase, lysozyme, vitamin-B12 binding proteins, plasminogen activator.

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c) Tertiary granules or C particles contain gelatinase and acid hydrolases. Myeloperoxidase
causes oxidative lysis by generation of oxygen free radicals, acid hydrolases act within the
cell to cause destruction of bacteria in phagolysosome while proteases attack on the
extracellular constituents such as basement membrane, collagen, elastin, cartilage etc.
ii) Granules of monocytes and tissue macrophages. These cells on degranulation also
release mediators of inflammation like acid proteases, collagenase, elastase and plasminogen
activator. They are more active in chronic inflammation.
4. PLATELET ACTIVATING FACTOR (PAF). It is released from IgE-sensitised
basophils or mast cells, other leucocytes, endothelium and platelets. Platelet aggregation,
release reaction and act as mediator of inflammation. They increase vascular permeability,
results in vasodilatation in low concentration, vasoconstriction, bronchoconstriction, adhesion
of leucocytes to endothelium; and chemotaxis.
5. CYTOKINES. Cytokines are polypeptide substances produced by activated lymphocytes
(lymphokines) and monocytes (monokines). Cytokines, which act as mediators of
inflammation are: interleukin-1 (IL-1), tumour necrosis factor (TNF)-α and β, interferon
(IFN)-γ, and chemokines (IL-8, PF-4). IL-1 and TNF-α are formed by activated macrophages
while TNF-β and IFN-γ are produced by activated T cells. The chemokines include
interleukin 8 (released from activated macrophages) and platelet factor-4 from activated
platelets, which are potent chemo-attractant for inflammatory cells.
i. IL-1 and TNF-α, TNF-β induce endothelial effects in the form of increased
leucocyte adherence, thrombogenicity, elaboration of other cytokines, fibroblastic
proliferation and acute phase reactions.
ii. IFN-γ causes activation of macrophages and neutrophils and is associated with
synthesis of nitric acid synthase.
iii. Chemokines are a family of chemo-attractants for inflammatory cells and include:
IL-8 chemotactic for neutrophils; platelet factor-4 chemotactic for neutrophils,
monocytes and eosinophils; MCP-1 chemotactic for monocytes; and eotaxin
chemotactic for eosinophils.
6. FREE RADICALS: OXYGEN METABOLITES AND NITRIC OXIDE.
Free radicals act as potent mediator of inflammation:
i. Oxygen-derived metabolites are released from activated neutrophils and
macrophages and include superoxide oxygen (O’2), H2O2, OH’ and toxic NO
products causes endothelial cell damage and increased vascular permeability.
Activation of protease and inactivation of antiprotease causing tissue matrix
damage.
ii. Nitric oxide (NO) is a vascular relaxation factor produced by endothelial cells. NO
is formed by activated macrophages during the oxidation of arginine by the action

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of enzyme, NO synthase. NO plays role in mediating inflammation by
Vasodilatation, Anti-platelet activating agent with microbicidal action.
II. Plasma-derived Mediators (Plasma Proteases):
These include activation and interaction of 4 interlinked systems: kinin, clotting, fibrinolytic
and complement. Hageman factor (factor XII) of clotting system plays a key role in
interactions of the four systems.
1. THE KININ SYSTEM. This system on activation by factor Xlla generates bradykinin
(slow contraction of smooth muscle),. First, kallikrein is formed from plasma prekallikrein by
the action of prekallikrein activator which is a fragment of factor Xlla. Kallikrein then acts on
high molecular weight kininogen to form bradykinin. It acts in the early stage of
inflammation and effects include: smooth muscle contraction; vasodilatation; increased
vascular permeability; and pain.
2. THE 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. The actions of fibrinopeptides in inflammation are: increased vascular
permeability; chemotaxis for leucocyte; and anticoagulant activity.
3. THE FIBRINOLYTIC SYSTEM. This system is activated by plasminogen activator, the
sources of which include kallikrein of the kinin system, endothelial cells and 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 actions of plasmin in inflammation are: activation of factor XII to form
prekallikrein activator that stimulates the kinin system to generate bradykinin; splits off

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complement C3 to form C3a which is a permeability factor; and degrades fibrin to form fibrin
split products which increase vascular permeability and are chemotactic to leucocytes.
4. THE COMPLEMENT SYSTEM. The activation of complement system can occur either:
i. By classic pathway through antigen-antibody complexes; or
ii. By alternate pathway via non-immunologic agents such as bacterial toxins, cobra
venoms and IgA.
Complement system on activation by either of these two pathways yields activated products
which include anaphylatoxins (C3a, C4a and C5a), and membrane attack complexes (MAC)
i.e. C5b, C6, 7, 8, 9. The actions of activated complement system in inflammation are: C3a,
C5a, C4a (anaphylatoxins) activate mast cells and basophils to release of histamine, because
increased vascular permeability causes oedema in tissues, augments phagocytosis. C3b is an
opsonin. C5a is chemotactic for leucocytes. Membrane attack complexes (MAC) (C5b-C9)
are lipid dissolving agents and form holes in the phospholipid membrane of the cells.
THE INFLAMMATORY CELLS
The cells participating in acute and chronic inflammation are circulating leucocytes, plasma
cells and tissue macrophages.

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1. Polymorphonuclear Neutrophil (PMN).
Commonly called as neutrophils or polymorphs, these cells along with basophils and
eosinophils are known as granulocytes due to the presence of granules in the cytoplasm.
These granules contain many substances like proteases, myeloperoxidase, lysozyme, esterase,
aryl sulfatase, acid and alkaline phosphatase and cationic proteins. These cells comprise 40-
75% of circulating leucocytes and their number is increased in blood (neutrophilia) and
tissues in acute bacterial infections. The functions of neutrophils in inflammation are:
i. Initial phagocytosis of microorganisms as they form the first 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 and degradation of the foreign material.
ii. Engulfment of antigen-antibody complexes and nonmicrobial material.
iii. Harmful effect of neutrophils in causing basement membrane destruction of the
glomeruli and small blood vessels.
2. Eosinophil.
These are larger than neutrophils but are fewer in number, comprising 1 to 6% of total blood
leucocytes. Eosinophils share many structural and functional similarities with neutrophils like
their production in the bone marrow, locomotion, phagocytosis, lobed nucleus and presence
of granules in the cytoplasm containing a variety of enzymes, of which major basic protein
and eosinophil cationic protein are the most important which have bactericidal and toxic
action against helminthic parasites. However, granules of eosinophils are richer in
myeloperoxidase than neutrophils and lack lysozyme. High level of steroid hormones leads to
fall in number of eosinophils and even disappearance from blood. The absolute number of
eosinophils is increased in inflammatory responses associated with these conditions:
i. Allergic conditions;
ii. Parasitic infestations;
iii. Skin diseases; and
iv. Certain malignant lymphomas.
3. Basophil (Mast Cells).
The basophils comprise about 1% of circulating leucocytes and are morphologically and
pharmacologically similar to mast cells of tissue. These cells contain coarse basophilic
granules in the cytoplasm and a polymorphonuclear nucleus. These granules are laden with
heparin and histamine. Basophils and mast cells have receptors for IgE and degranulate when
cross-linked with antigen. The roles of these cells in inflammation are:
i. In immediate and delayed type of hypersensitivity reactions; and
ii. Release of histamine by IgE-sensitised basophils.

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4. Lymphocyte.
Next to neutrophils, these cells are the most numerous of the circulating leucocytes (20-45%).
Apart from blood, lymphocytes are present in large numbers in spleen, thymus, lymph nodes
and mucosa-associated lymphoid tissue (MALT). They have scanty cytoplasm and consist
almost entirely of nucleus. Their role in antibody formation (B lymphocytes) and in cell-
mediated immunity in addition these cells participate in inflammatory responses:
i. In tissues, they are dominant cells in chronic inflammation and late stage of acute
inflammation.
ii. In blood, their number is increased (lymphocytosis) in chronic infections like
tuberculosis.
5. Plasma Cells
These cells are larger than lymphocytes with more abundant cytoplasm and an eccentric
nucleus which has cart-wheel pattern of chromatin. Plasma cells are normally not seen in
peripheral blood. They develop from B lymphocytes and are rich in RNA and γ-globulin in
their cytoplasm. There is an interrelationship between plasmacytosis and hyperglobulinaemia.
These cells are most active in antibody synthesis. Their number is increased in the following
conditions: Prolonged infection with immunological responses e.g. in syphilis, rheumatoid
arthritis, tuberculosis etc…
6. Mononuclear-Phagocyte System (Reticuloendothelial System).
This cell system includes cells derived from 2 sources with common morphology, function
and origin. These are as under:
Blood monocytes. These comprise 4-8% of circulating leucocytes.
Tissue macrophages. These include the following cells in different tissues:
i. Macrophages in inflammation.
ii. Histiocytes which are macrophages present in connective tissues.
iii. Kupffer cells are macrophages of liver cells.
iv. Alveolar macrophages (type II pneumocytes) in lungs.
v. Macrophages/histiocytes of the bone marrow.
vi. Tingible body cells of germinal centres of lymph nodes.
vii. Littoral cells of splenic sinusoids.
viii. Osteoclasts in the bones.
ix. Microglial cells of the brain.
x. Langerhans’ cells/dendritic histiocytes of the skin.
xi. Hoffbauer cells of the placenta.
xii. Mesangial cells of glomerulus.

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Role of macrophages in inflammation. The functions of mononuclear-phagocyte cells are
as under:
i. Phagocytosis (cell eating) and pinocytosis (cell drinking).
ii. Macrophages on activation by lymphokines released by T lymphocytes or by non-
immunologic stimuli produces a variety of biologically active substances:
a. Proteases like collagenase and elastase which degrade collagen and elastic
tissue.
b. Plasminogen activator which activates the fibrinolytic system.
c. Products of complement.
d. Some coagulation factors (factor V and thromboplastin) which convert
fibrinogen to fibrin.
e. Chemotactic agents for other leucocytes.
f. Metabolites of arachidonic acid.
g. Growth promoting factors for fibroblasts, blood vessels and granulocytes.
h. Cytokines like interleukin-1 and TNF-α.
i. Oxygen-derived free radicals.
7. Giant Cells.
Multinucleate giant cells exist in normal tissues (e.g. osteoclasts in the bones, trophoblasts in
placenta and megakaryocytes in the bone marrow). In chronic inflammation when the
macrophages fail they fuse together and form multinucleated giant cells.
FACTORS DETERMINING VARIATION IN INFLAMMATORY RESPONSE
Although acute inflammation is typically characterised by vascular and cellular events with
emigration of neutrophilic leucocytes, not all examples of acute inflammation show
infiltration by neutrophils. On the other hand, some chronic inflammatory conditions are
characterised by neutrophilic infiltration. For example, typhoid fever is an example of acute
inflammatory process but the cellular response in it is lymphocytic; osteomyelitis is an
example of chronic inflammation but the cellular response in this condition is mainly
neutrophilic. The variation in inflammatory response depends upon a number of factors and
processes.
1. Factors Involving the Organisms
i. Type of injury and infection. For example, skin reacts to herpes simplex infection
by formation of vesicle and to streptococcal infection by formation of boil; lung reacts
to pneumococci by occurrence of lobar pneumonia while to tubercle bacilli it reacts
by granulomatous inflammation.
ii. Virulence. Many species and strains of organisms may have varying virulence e.g.
the three strains of C. diphtheria (gravis, intermedius and mitis) produce the same
diphtheria exotoxin but in different amount.

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iii. Dose. The concentration of organism in small doses produces usually local lesions
while larger dose results in more severe spreading infections.
iv. Portal of entry. Some organisms are infective only if administered by particular route
e.g. Vibrio cholerae is not pathogenic if injected subcutaneously but causes cholera if
swallowed.
v. Product of organisms. Some organisms produce enzymes that help in spread of
infections e.g. hyaluronidase by Clostridium welchii, streptokinase by streptococci,
staphylokinase and coagulase by staphylococci.
2. Factors Involving the Host
i. Systemic diseases. Certain acquired systemic diseases in the host are associated with
impaired inflammatory response e.g. diabetes mellitus, chronic renal failure, cirrhosis
of the liver, chronic alcoholism, bone marrow suppression from various causes (drugs,
radiation, idiopathic). These conditions render the host more susceptible to infections.
ii. Immune status of host. Patients who are immunosuppressed from congenital or
acquired immunodeficiency have lowered inflammatory response and spread of
infections occurs rapidly e.g. in AIDS, congenital immunodeficiency diseases, protein
calorie malnutrition, starvation.
iii. Congenital neutrophil defects. Congenital defects in neutrophil structure and
functions result in reduced inflammatory response.
iv. Leukopenia. Patients with low WBC count with neutropenia or agranulocytosis
develop spreading infection.
v. Site or type of tissue involved. For example, the lung has loose texture as compared
to bone and, thus, both tissues react differently to acute inflammation.
vi. Local host factors. For instance, ischaemia, presence of foreign bodies and chemicals
cause necrosis and are thus cause more harm.
3. Type of Exudation
The appearance of escaped plasma determines the morphologic type of inflammation as
under:
i. Serous, when the fluid exudate resembles serum or is watery e.g. pleural effusion in
tuberculosis, blister formation in burns.
ii. Fibrinous, when the fibrin content of the fluid exudate is high e.g. in pneumococcal
and rheumatic pericarditis.
iii. Purulent or suppurative exudate is formation of creamy pus as seen in infection
with pyogenic bacteria e.g. abscess, acute appendicitis.
iv. Haemorrhagic, when there is vascular damage e.g. acute haemorrhagic pneumonia in
influenza.
v. Catarrhal, when the surface inflammation of epithelium produces increased secretion
of mucous e.g. common cold.

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MORPHOLOGY OF ACUTE INFLAMMATION
Inflammation of an organ is usually named by adding the suffix-itis to its Latin name e.g.
appendicitis, hepatitis, cholecystitis, meningitis etc. A few morphologic varieties of acute
inflammation are described below:
1. PSEUDOMEMBRANOUS INFLAMMATION. It is inflammatory response of mucous
surface (oral, respiratory, bowel) to toxins of diphtheria or irritant gases. As a result of
denudation of epithelium, plasma exudes on the surface where it coagulates, and together
with necrosed epithelium, forms false membrane.
2. ULCER. Ulcers are local defects on the surface of an organ produced by inflammation.
Common sites for ulcerations are the stomach, duodenum, intestinal ulcers in typhoid fever,
intestinal tuberculosis, bacillary and amoebic dysentery, ulcers of legs due to varicose veins
etc.
3. SUPPURATION (ABSCESS FORMATION). When acute bacterial infection is
accompanied by intense neutrophilic infiltrate in the inflamed tissue, it results in tissue
necrosis. A cavity is formed which is called an abscess and contains pus and the process of
abscess formation is known as suppuration. The bacteria which cause suppuration are called
pyogenic.
Microscopically, pus is creamy or opaque in appearance and is composed of numerous dead
as well as living neutrophils, some red cells, fragments of tissue debris and fibrin. An abscess
may be discharged to the surface due to increased pressure inside or may require drainage by
the surgeon. Due to tissue destruction, resolution does not occur but instead healing by
fibrous scarring takes place. Some of the common examples of abscess formation are:
i. Boil or furruncle which is an acute inflammation via hair follicles in the dermal
tissues.
ii. Carbuncle is seen in untreated diabetics and occurs as a loculated abscess in the
dermis and soft tissues of the neck.
4. CELLULITIS. It is a diffuse inflammation of soft tissues resulting from spreading effects
of substances like hyaluronidase released by some bacteria.
5. BACTERIAL INFECTION OF THE BLOOD. This includes the 3 conditions:
i. Bacteraemia is defined as presence of small number of bacteria in the blood which
do not multiply significantly. E.g. infection with Salmonella typhi, Escherichia coli,
Streptococcus viridans.
ii. Septicaemia means presence of rapidly multiplying, highly pathogenic bacteria in
the blood e.g. pyogenic cocci, bacilli of plague etc. Septicaemia is generally
accompanied by systemic effects like toxaemia, multiple small haemorrhages,
neutrophilic leucocytosis and disseminated intravascular coagulation (DIC).

20
iii. Pyaemia is the dissemination of small septic thrombi in the blood which cause their
effects at the site where they are lodged. This can result in pyaemic abscesses or
septic infarcts.
a. Pyaemic abscesses are multiple small abscesses in various organs such as in
cerebral cortex, myocardium, lungs and renal cortex, resulting from very small
emboli fragmented from septic thrombus. Microscopy of pyaemic abscess
shows a central zone of necrosis containing numerous bacteria, surrounded by a
zone of suppuration and an outer zone of acute inflammatory cells.
b. Septic infarcts result from lodgement of larger fragments of septic thrombi in
the arteries with relatively larger foci of necrosis, suppuration and acute
inflammation e.g. septic infarcts of the lungs, liver, brain, and kidneys from
septic thrombi of leg veins or from acute bacterial endocarditis.
SYSTEMIC EFFECTS OF ACUTE INFLAMMATION
Acute inflammation is associated with systemic effects which include fever, leucocytosis,
lymphangitis and lymphadenitis.
1. Fever occurs due to bacteraemia. It is mediated through release of factors like
prostaglandins, interleukin-1 and TNF-α in response to infection.
2. Leucocytosis commonly accompanies the acute inflammatory reactions, usually in
the range of 15,000- 20,000/μl. In bacterial infections there is an abscess in the skin. It
contains pus composed of necrotic tissue, debris, fibrin, RBCs and dead and living
neutrophils. Some macrophages are seen at the periphery neutrophilia; in viral
infections lymphocytosis; and in parasitic infestations, eosinophilia. Typhoid fever, an
example of acute inflammation, induces leucopenia with relative lymphocytosis.
3. Lymphangitis-lymphadenitis is one of the important manifestations of localised
inflammatory injury. The lymphatics and lymph nodes that drain the inflamed tissue
show reactive inflammatory changes in the form of lymphangitis and lymphadenitis.
The affected lymph nodes may show hyperplasia of lymphoid follicles (follicular
hyperplasia) and proliferation of mononuclear phagocytic cells in the sinuses of
lymph node (sinus histiocytosis).
4. Shock may occur in severe cases. Massive release of cytokine TNF-α, a mediator of
inflammation, in response to severe tissue injury or infection results in profuse
systemic vasodilatation, increased vascular permeability and intravascular volume
loss. The net effect of these changes is hypotension and shock. Systemic activation of
coagulation pathway may lead to microthrombi throughout the body. It results in
disseminated intravascular coagulation (DIC), bleeding and death.
FATE OF ACUTE INFLAMMATION
The acute inflammatory process involves:

21
1. Resolution. It means complete return to normal tissue following acute inflammation.
This occurs when tissue changes are slight and the cellular changes are reversible e.g.
resolution in lobar pneumonia.
2. Healing. Healing by fibrosis takes place when the tissue destruction in acute
inflammation is extensive so that there is no tissue regeneration. But when tissue loss
is superficial, it is restored by regeneration.
3. Suppuration. When the pyogenic bacteria causing acute inflammation result in
severe tissue necrosis, the process progresses to suppuration. Initially, intense
neutrophilic infiltration followed by mixture of neutrophils, bacteria, fragments of
necrotic tissue, cell debris and fibrin comprise pus which is contained in a cavity to
form an abscess. The abscess, get organised by dense fibrous tissue, and get calcified.
4. Chronic inflammation. Persisting or recurrent acute inflammation may progress to
chronic inflammation in which the processes of inflammation and healing proceed
side by side.
CHRONIC INFLAMMATION
Definition and causes. Chronic inflammation is defined as prolonged process in which tissue
destruction and inflammation occur at the same time. Chronic inflammation can be caused by
3 ways:
1. Chronic inflammation following acute inflammation. When the tissue destruction
is extensive, or the bacteria survive and persist in small numbers at the site of acute
inflammation e.g. in osteomyelitis, pneumonia terminating in lung abscess.
2. Recurrent attacks of acute inflammation. Repeated occurring of acute
inflammation increase chronicity of the process e.g. in recurrent urinary tract infection
leading to chronic pyelonephritis, 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.
GENERAL FEATURES OF CHRONIC INFLAMMATION
1. MONONUCLEAR CELL INFILTRATION. Chronic inflammatory lesions are
infiltrated by mononuclear inflammatory cells like phagocytes and lymphoid cells.
Phagocytes are represented by circulating monocytes, tissue macrophages, epithelioid cells
and sometimes, multinucleated giant cells. The macrophages comprise the most important
cells in chronic inflammation. These may appear at the site of chronic inflammation from:
i. Chemotactic factors and adhesion molecules for continued infiltration of
macrophages;
ii. Local proliferation of macrophages; and
iii. Longer survival of macrophages at the site of inflammation.

22
The blood monocytes on reaching the extravascular space transform into tissue macrophages.
On activation, macrophages release several biologically active substances e.g. acid and
neutral proteases, oxygen-derived reactive metabolites and cytokines which bring about
tissue destruction, neovascularisation and fibrosis. Other chronic inflammatory cells include
lymphocytes, plasma cells, eosinophils and mast cells.
2. TISSUE DESTRUCTION OR NECROSIS. Tissue destruction and necrosis are brought
about by activated macrophages which release a variety of biologically active substances e.g.
protease, elastase, collagenase, lipase, reactive oxygen radicals, cytokines (IL-1, IL-8, TNF-
α), nitric oxide, angiogenesis growth factor etc.
3. PROLIFERATIVE CHANGES. As a result of necrosis, proliferation of small blood
vessels and fibroblasts is stimulated resulting in formation of inflammatory granulation
tissue. Eventually, healing by fibrosis and collagen laying takes place.
SYSTEMIC EFFECTS OF CHRONIC INFLAMMATION
Chronic inflammation is associated with features like:
1. Fever. Invariably there is mild fever, often with loss of weight and weakness.
2. Anaemia. Chronic inflammation is accompanied by anaemia of varying degree.
3. Leucocytosis. As in acute inflammation, chronic inflammation also has leucocytosis
but generally there is relative lymphocytosis in these cases.
4. ESR. ESR is elevated in all cases of chronic inflammation.
5. Amyloidosis. Long-term cases of chronic suppurative inflammation may develop
secondary systemic (AA) amyloidosis.
TYPES OF CHRONIC INFLAMMATION
Chronic inflammation is subdivided into 2 types:
1. Non-specific, when the irritant substance produces a nonspecific chronic inflammatory
reaction with formation of granulation tissue and healing by fibrosis e.g. chronic
osteomyelitis, chronic ulcer.
2. Specific, when the injurious agent causes a characteristic histologic tissue response e.g.
tuberculosis, leprosy, syphilis. Histological features classify chronic inflammation into 2
types:
i. Chronic non-specific inflammation. It is characterised by non-specific
inflammatory cell infiltration e.g. chronic osteomyelitis, lung abscess. Chronic
suppurative inflammation in which infiltration by polymorphs and abscess
formation are additional features e.g. actinomycosis.
ii. Chronic granulomatous inflammation. It is characterised by formation of
granulomas e.g. tuberculosis, leprosy, syphilis, actinomycosis, sarcoidosis etc.

23
HEALING
Healing is the body response in injury to restore normal structure and function.
Healing involves 2 processes:
Regeneration: Healing takes place by proliferation of parenchymal cells and complete
restoration of the original tissues.
Repair: Healing takes place by proliferation of connective tissue resulting in fibrosis and
scarring.
At times, both the processes take place simultaneously.
REGENERATION:
To maintain proper structure of tissues, cells are under the regulatory control of their
cell cycle. These include growth factors such as: epidermal growth factor, fibroblast growth
factor, platelet derived growth factor, endothelial growth factor, transforming growth factor.
REPAIR:
It is the replacement of injured tissue by fibrous tissue. The processes involved in
repair are:
1. Granulation tissue formation; and
2. Contraction of wounds.
Repair response takes place by mesenchymal cells (consisting of connective tissue
stem cells, fibrocytes and histiocytes), endothelial cells, macrophages, platelets, and the
parenchymal cells of the injured organ.
Granulation Tissue Formation
Granulation tissue (granular and pink appearance of the tissue). Granule corresponds
histologically to proliferation of new small blood vessels. The 3 phases observed in the
formation of granulation tissue are:
1. PHASE OF INFLAMMATION. Following trauma, blood clots at the site of injury.
There is acute inflammatory response with exudation of plasma, neutrophils and monocytes
within 24 hours.
2. PHASE OF CLEARANCE. Combination of proteolytic enzymes liberated from
neutrophils, autolytic enzymes from dead tissues cells, and phagocytic activity of
macrophages clear off the necrotic tissue, debris and red blood cells.
3. PHASE OF INGROWTH OF GRANULATION TISSUE. This phase consists of 2
main processes: angiogenesis or neovascularisation, and fibrogenesis.
i) Angiogenesis (neovascularisation). Formation of new blood vessels at the site of
injury takes place by proliferation of endothelial cells from the margins of blood

24
vessels and within a few hours they develop lumen and start carrying blood. They are
leaky. These blood vessels differentiate into muscular arterioles, thin-walled venules
and true capillaries. Angiogenesis is stimulated with the proteolytic destruction of
basement membrane and takes place under the influence of:
a) Vascular endothelial growth factor (VEGF) its receptors are present in endothelial
cells only.
b) Platelet-derived growth factor (PDGF), transforming growth factor-β(TGF-β),
basic fibroblast growth factor (bFGF) and surface integrins. Associated with
cellular proliferation.
ii) Fibrogenesis. The newly formed blood vessels may also originate from fibrocytes by
mitotic division of fibroblasts. These fibroblasts have combination of morphologic
and functional characteristics of smooth muscle cells (myofibroblasts). Collagen
fibrils begin to appear by about 6th day. As maturation proceeds, more and more of
collagen is formed while the number of active fibroblasts and new blood vessels
decreases. This results in formation of inactive looking scar known as cicatrisation.
Contraction of Wounds
The wound starts contracting after 2-3 days and the process is completed by the 14th
day and the wound is reduced by 80% of its original size. Contracted wound results in rapid
healing due to lesser surface area of the injured tissue. The mechanism of wound contraction
and factors involved are:
1. Dehydration as a result of removal of fluid by drying of wound.
2. Contraction of collagen was responsible for wound contraction.
3. Myofibroblasts cells migration into the wound area and contraction decreases the size
of the defect.
i. Fibrils present in the cytoplasm as seen in smooth muscle cells.
ii. These cells contain actin-myosin as found in non-striated muscle cells.
iii. These cells have basement membrane and desmosomes which are not seen in
ordinary fibroblasts.
iv. Drug response of granulation tissue is similar to that of smooth muscle.
WOUND HEALING
Healing of skin wounds is a combination of regeneration and repair Wound healing
takes place by one of the two ways:
a. Healing by first intention (primary union)
b. Healing by second intention (secondary union).
a. Healing by First Intention (Primary Union)
Healing of a wound with these characteristics occurs by Healing by First Intention
(Primary Union):
i) Clean and uninfected;
ii) Surgically incised;
iii) Without much loss of cells and tissue;
iv) Edges of wound are approximated by surgical sutures.

25
1. Initial haemorrhage. Immediately after injury, the space between the approximated
surfaces of incised wound is filled with blood which then clots and seals the wound against
dehydration and infection.
2. Acute inflammatory response. This occurs within 24 hours with appearance of
polymorphs from the margins of incision. By 3rd day, polymorphs are replaced by
macrophages.
3. Epithelial changes. The basal cells of epidermis from both the cut margins start
proliferating and migrating towards incisional space in the form of epithelial spurs. A well
approximated wound is covered by a layer of epithelium in 48 hours. The migrated epidermal
cells, necrotic material and clot, forming scab. The basal cells from the margins continue to
divide and by 5th day, a multi-layered new epidermis is formed.
4. Organisation. By 3rd day, fibroblasts also invade the wound area. By 5th day, new
collagen fibrils start forming which dominate till healing is completed. In 4 weeks, the scar
tissue with scanty cellular and vascular elements, a few inflammatory cells and epithelialised
surface is formed.
5. Suture tracks. It is a separate wound due to suture. The suture track gets infected (stitch
abscess), or the epithelial cells may persist in the track (implantation or epidermal cysts).
Scar formed in a sutured wound is neat.
b. Healing by Second Intention (Secondary Union)
Healing of a wound with characteristics occurs by Healing by Second Intention
(Secondary Union):
i) Open with a large tissue defect, at times infected;
ii) Having extensive loss of cells and tissues;
iii) The wound is not approximated by surgical sutures but is left open.
The basic events in secondary union are similar to primary union but differ in having a larger
tissue defect which has to be bridged. Hence healing takes place from the base upwards as

26
well as from the margins inwards. The healing by second intention is slow and results in a
large, at times ugly scar.
1. Initial haemorrhage. As a result of injury, the wound space is filled with blood and fibrin
clot which dries.
2. Inflammatory phase. There is an initial acute inflammatory response followed by
appearance of macrophages which clear off the debris as in primary union.
3. Epithelial changes. As in primary healing, the epidermal cells from both the margins of
wound proliferate and migrate into the wound in the form of epithelial spurs till they meet in
the middle and re-epithelialise the gap completely. The regenerated epidermis becomes
stratified and keratinised.
4. Granulation tissue. Granulation tissue is formed by proliferation of fibroblasts and
neovascularisation. The newly-formed granulation tissue is deep red, granular and very
fragile, the scar on maturation becomes pale and white due to increase in collagen and
decrease in vascularity.
5. Wound contraction. Contraction of wound is an important feature of secondary healing,
not seen in primary healing. Due to myofibroblasts present in granulation tissue, the wound
contracts to one-third to one-fourth of its original size. Wound contraction occurs at a time
when active granulation tissue is being formed.
6. Presence of infection. Bacterial contamination of an open wound delays the process of
healing due to release of bacterial toxins that provoke necrosis, suppuration and thrombosis.
Surgical removal of dead and necropsied tissue debridement helps in preventing the bacterial
infection of open wounds.

27
Complications of Wound Healing
Complications includes:
1. Infection of wound due to entry of bacteria delays the healing.
2. Implantation (epidermal) cyst formation may occur due to persistence of epithelial
cells in the wound after healing.
3. Pigmentation. Healed wounds may at times have rust-like colour due to staining with
haemosiderin. Some coloured particulate material left in the wound may persist and
impart colour to the healed wound.
4. Deficient scar formation. This may occur due to inadequate formation of granulation
tissue.
5. Incisional hernia. A weak scar, especially after a laparotomy, may be the site of
bursting open of a wound (wound dehiscence) or an incisional hernia.
6. Hypertrophied scars and keloid formation. At times the scar formed is excessive, ugly
and painful. Excessive formation of collagen in healing may result in keloid (claw-
like) formation, seen more commonly in Blacks.
7. Excessive contraction. An exaggeration of wound contraction may result in formation
of contractures or cicatrisation e.g. Dupuytren’s (palmar) contracture, plantar
contracture and Peyronie’s disease (contraction of the cavernous tissues of penis).
8. Neoplasia. Rarely, scar may be the site for development of carcinoma later e.g.
squamous cell carcinoma in Marjolin’s ulcer i.e. a scar following burns on the skin.
Extracellular Matrix—Wound Strength
The wound is strengthened by proliferation of fibroblasts and myofibroblasts which
get structural support from the extracellular matrix (ECM). ECM can direct cell migration,
attachment, differentiation and organisation. ECM has five main components: collagen,
adhesive glycoproteins, basement membrane, elastic fibres, and proteoglycans.
1. COLLAGEN. The collagens are a family of proteins which provide structural support. It
is the main component of tissues such as fibrous tissue, bone, cartilage, valves of heart,
cornea, basement membrane etc. Defective regulation of collagen synthesis leads to
hypertrophied scar, fibrosis, and organ dysfunction.
2. ADHESIVE GLYCOPROTEINS. Various adhesive glycoproteins acting as glue for the
ECM and the cells consist of fibronectin, tenascin (cytotactin) and thrombospondin.
i) Fibronectin (nectere = to bind) is the best glycoprotein in ECM and It is of two types-
plasma and tissue fibronectin.
Plasma fibronectin is synthesised by the liver cells and is trapped in basement membrane.
Tissue fibronectin is formed by fibroblasts, endothelial cells and other mesenchymal cells.
ii) Tenascin or cytotactin is the glycoprotein associated with fibroblasts and appears in
wound about 48 hours after injury. It disappears from mature scar tissue.
iii) Thrombospondin is mainly synthesised by granules of platelets. It functions as
adhesive protein for keratinocytes and platelets.

28
3. BASEMENT MEMBRANE. Basement membranes are structures that lie underneath
epithelia of different organs and endothelial cells.
4. ELASTIC FIBRES. Elastic fibres consist of 2 components—elastin glycoprotein and
elastic microfibril. Elastases degrade the elastic tissue e.g. in inflammation, emphysema etc.
5. PROTEOGLYCANS. These have 2 components—an essential carbohydrate polymer
(called polysaccharide or glycosaminoglycan), and a protein bound to it. Various
proteoglycans are:
i) Chondroitin sulphate—abundant in cartilage, dermis
ii) Heparan sulphate—in basement membranes
iii) Dermatan sulphate—in dermis
iv) Keratan sulphate—in cartilage
v) Hyaluronic acid—in cartilage, dermis.
Factors Influencing Healing
Two types of factors influence the wound healing: those acting locally, and those
acting in general.
A. LOCAL FACTORS:
1. Infection is the most important factor acting locally which delays the process of
healing.
2. Poor blood supply to wound slows healing e.g. injuries to face heal quickly due to
rich blood supply while injury to leg with varicose ulcers having poor blood supply
heals slowly.
3. Foreign bodies including sutures interfere with healing and cause intense
inflammatory reaction and infection.
4. Movement delays wound healing.
5. Exposure to ionising radiation delays granulation tissue formation.
6. Exposure to ultraviolet light facilitates healing.
7. Type, size and location of injury determine whether healing takes place by resolution
or organisation.
B. SYSTEMIC FACTORS:
1. Age. Wound healing is rapid in young and somewhat slow in aged and debilitated
people due to poor blood supply to the injured area in the latter.
2. Nutrition. Deficiency of constituents like protein, vitamin C (scurvy) and zinc delays
the wound healing.
3. Systemic infection delays wound healing.
4. Administration of glucocorticoids has anti-inflammatory effect.
5. Uncontrolled diabetics are more prone to develop infections and hence delay in
healing.
6. Hematologic abnormalities like defect of neutrophil functions (chemotaxis and
phagocytosis), and neutropenia and bleeding disorders slow the process of wound
healing.

INFLAMMATION PATHOPHYSIOLOGY

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