INFLAMMATION AND HEALING

Inflammation

“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, followed by removal of the necrosed cells and tissues.
Agents causing inflammation

1) Infective agents - bacteria, viruses and their toxins, fungi,

parasites
2) Immunological agents - cell mediated and antigen antibody
reactions.
3) Physical agents - heat, cold, radiation, mechanical trauma
4) Chemical agents - organic and inorganic poisons.
5) Inert materials - foreign bodies.
Signs of inflammation
(Celsus in 1st Century AD)

1) Rubor (redness).
2) tumor (swelling).
3) calor (heat).
4) dolar (pain).
5) functiolesa (loss of function) which was later added by Virchow.
Types of Inflammation (defence capacity of the host & duration of
response)

• Acute
• Chronic
Acute
• < 2weeks
• Resolves quickly
• Healing

Fluid and plasma accumulation; activation of

platelets; polymorphonucleur neutrophils

• Fulminant Acute Inflammation

Chronic Inflammation
• Causative agent for long time
• Mild stimulus

lymphocytes, plasma cells and macrophages,

granulation tissue formation/ granulomatous
inflammation.
Acute Inflammatory Response

Vascular events

Cellular events
Vascular Changes

Alteration in the microvasculature (arterioles, capillaries and venules)

Haemodynamic Vascular
Changes Permeability
Haemodynamic Changes
vascular flow and calibre of small blood vessels in the injured
tissues

• Persistant/progressive vasodilation
• redness and warmth
• Increased local hydrostatic pressure
• Transudation of fluid into cellular space – swelling
• Increased viscosity of the blood
• Leucocytic margination and emigration
 Lewis Expriment

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Vascular Permeability
The appearance of inflammatory oedema is due to increased vascular
permeability of microvascular bed and is explained on the basis of
Starlings hypothesis.
In normal circumstances a fluid balance is maintained by 2 opposing
sets of forces.
• intravascular hydrostatic pressure
• colloid osmotic pressure
Mechanism of increased vascular permeability

• Contraction of endothelial cells

• Retraction of the endothelial cells
• Direct injury to the endothelial cells
• Endothelial injury mediated by leucocytes
• Leakiness due to neovascularisation
Contraction of the endothelial cells:
• Occurs in venules
• Temporary gap between the endothelial cells
• Mediated by histamine and bradykinin
• Initiated immediately
• Eg: mild thermal injury of the forearm
Retraction of the endothelial cells
• Structural reorganisation of endothelial cells
• Affects venules
• cytokines like IL-1 and TNF-α.
• Initiated 4-6 hours after injury and lasts 2-4 hours
Direct injury to endothelial cells
• causes cell necrosis and appearance of physical gaps at the sites of
detached endothelial cells.
• Process of thrombosis initiated at the site of damaged endothelial cells.
• The increased permeability may either appear immediately after injury
and last for several hrs or days
Endothelial injury mediated by leucocytes
• Adherence of leucocytes to endothelium release proteolytic enzymes
and toxic oxygen species.
• Effects mostly venules eg: in pulmonary venules and capillaries.
• Leakiness in neovascularisation:
Cellular changes

Cellular Phase of Inflammation

• Exudation of leucocytes
• Phagocytosis
Exudation of leucocytes –
• Escape from lumen to interstitial tissue
• In acute inflammation PMN – first line of response ans the Monocytes
and Macrophages
The sequence

1. Changes in the formed elements of blood

2. Rolling and Adhesion
3. Emigration
4. Chemotaxis

Cells escape from blood vessels to perivascular tissue by pseudopod formation

Chemotaxis is unidirectional migration of cells towards an attractant like bacterial products,
components of endothelial system

Phagocytosis and degranulation

1. Changes in the formed elements of blood
Vasodialation - rate of flow is more
Slowing/statsis of blood stream
Normal axial flow – central stream – leucocytes & RBCs
Peripheral cell free layer of plasma
Due to slowing – perpipheral plasma zone becomes narrower due to plasma loss –
exudation
Margination
2. Rolling and Adhesion
Neutrophils slowly roll over the endothelial cells followed by bond between the leucocytes and endothelial
cells becoming firmer
The following cell adhesion molecules (CAM)s bring about rolling and adhesion phase
Selectins
Found on the surface of endothelial cells
Recognise and bind to glycoproteins and glycolipids in the cell surface of neutrophils
3 types of selectins
P-selectin - rolling
E-selectin – rolling and adhesion
L-selectin – homing in lymph nodes
Integrins
Acivated adhesion between endothelial cells and leucocytes
Receptors for integrins on neutrophils are also stimulated
Firm adhesion between leucocytes and endothelium
Immunoglobulin gene superfamily adhesion molecule
They have a role in recognition and binding of immunocompetent cells
3. Emigration
After neutrophils stick to the endothelium, they move along the surface to find the suitable site, once
found they throw out pseudopods.
Neutrophils cross the basement membrane by secreting collagenases and escape into the
extravascular space
Neutrophils are dominant inflammatory exudate in the first 24 hours followed by monocytes and
macrophages in the next 24 hours
Subsequent to the emigration, RBCs also escape – diapedeis (due to damage of endothelial cells or
increase in the hydrostatic pressure)
Diapedesis gives haemorrhagec appearance to the inflammatory exudate
4. CHEMOTAXIS
Transmission of leucocytes into the extravascular space is chemotactic factor mediated process
The following agents act as chemotactic substances:
• Leukotriene B4 – arachidonic acid metabolite –by ipooxygenase pathway
• Components of complement system – C5a and C3a
• Cytokins (interleukins – IL-8)
• Soluble bacterial products
Phagocytosis

• process of engulfment of solid particulate material by the cells (cell

eating)
• cells performing this function is called phagocytes

• There are 2 main types of phagocytic cells 1) PMN which appear

early in acute inflammatory responses, also called microphages. 2)
circulating monocytes and fixed tissue mononuclear phagocytes
commonly called as macrophages.
Different stages of phagocytosis

• Recognition and attachment with the help of IgG and C3b

• Engulfment – cytoplasmic pseudopod formation and engulfment
• Phagocytic vacuole formation and degranulation
• Phagolysosome formation after fusion with lysosome
Recognition and Attachment
appearance of surface receptors on macrophages which recognize micro organisms
e.g.: mannose receptors, scavenger receptor.
micro organisms are coated with specific proteins, opsonins, from the serum.
Opsonins establish a bond between bacteria and cell membrane.
IgG opsonin, C3b opsonin, lectins
Engulfment
formation of cytoplasmic pseudopods around the particle due to activation of actin
filaments beneath cell wall Phagosome is internalised
all, enveloping it in a phagocytic vacuole.
Phagosome fuses with the lysosome in the cell to form phagolysosome –.
Killing and Degradation
Ultimate aim of phagocytosis by two mechanisms
Oxygen dependent bactericidal mechanism
-Myeloperoxidase dependant klling
-Myeloperoxidase independent killing
Oxygen independent mechanisms
Lysozymes
Major Basic Proteins
Bactericidal Permeability Increasing Proteins
Lactoferrins
• A. INTRACELLULAR MECHANISMS.
• i) Oxidative bactericidal mechanism by oxygen free radicals.
• An important mechanism of microbicidal killing is by oxidative damage by the production of
reactive oxygen metabolites (O’2 H2O2, OH’, HOCl, HOI, HOBr).
• phase of increased oxygen consumption (‘respiratory burst’) by activated phagocytic leucocytes
requires the essential presence of NADPH oxidase.
This type of bactericidal activity is carried out either via enzyme myeloperoxidase (MPO) present in
the azurophilic granules of neutrophils and monocytes, or independent of enzyme MPO,
• a) MPO-dependent killing

• b) MPO-independent killing.
• iii) Non-oxidative bactericidal mechanism.

• Some agents released from the granules of phagocytic cells do not require oxygen for bactericidal
activity
a) Granules. Some of liberated lysosomal granules do not kill by oxidative damage but cause lysis
of within phagosome.
These are lysosomal hydrolases, permeability increasing factors, cationic proteins (defensins),
lipases, ptoteases, DNAases.
• b) Nitric oxide. Nitric oxide reactive free radicals similar to oxygen free radicals are formed by
nitric oxide synthase and is a potent mechanism of microbial killing. Nitric oxide is produced by
endothelial cells as well as by activated macrophages.
B. EXTRACELLULAR MECHANISMS.
i) Granules. Degranulation of macrophages and neutrophils explained above continues to exert its
effects of proteolysis outside the cells as well.
ii) Immune mechanisms. immune-mediated lysis of microbes takes place outside
the cells by mechanisms of cytolysis, antibody-mediated lysis and by cell-mediated cytotoxicity
Extracellular release leukocyte products
Oxygen derived active metabolites and products of arachidonic acid
metabolism occur in three ways
• Regurgitation
• Reverse endocytosis
• Cytotoxic release
Chemical Mediators of Inflammation
Large endogenous compounds which can increase the vascular
permeability.
They can also function in other ways other than acute inflammation
e.g. vasodilatation, chemotaxis, fever, pain and cause tissue
damage.
They may be released from the cells, plasma or damaged tissues
itself.
They can be broadly classified into
• Mediators released from cells
1. Vasoactive amines eg: histamine, 5-hydroxytryptamine
2. Arachidonic acid and its metabolites (eicosonoids).
• Metabolites via cyclooxygenase pathway (prostaglandins, thromboxane
A2, prostacyclin and resolvins).
• Metabolites via lipooxygenase pathway (5HETE, leucotrienes, lipoxins).

3. Lysosomal components (from PMNs, macrophages).

4. Platelet activating factor.
5. Cytokines (IL1,TNF alpha, beta, gamma,chemokines).
6. Free radicals (oxygen metabolites, nitric oxide).
Mediators released from plasma

1) The kinin system.

2) The clotting system
3) The fibrinolytic system
4) The complement system.
Chemical Mediators of Inflammation
permeability factors or endogenous mediators
of increased vascular permeability
Mediators also induce vasodilatation, chemotaxis, fever, pain
and cause tissue damage
• I. CELL-DERIVED MEDIATORS

• 1. Vasoactive amines
• (Histamine, 5-hydroxytryptamine, neuropeptides)
• 2. Arachidonic acid metabolites (Eicosanoids)
• i. Metabolites via cyclo-oxygenase pathway
• (prostaglandins, thromboxane A2, prostacyclin, resolvins)
• ii. Metabolites via lipo-oxygenase pathway
• (5-HETE, leukotrienes, lipoxins)
3. Lysosomal components (from PMNs, macrophages)
4. Platelet activating factor
5. Cytokines (IL-1, TNF-α, TNF-β, IFN-γ, chemokines)
6. Free radicals (Oxygen metabolites, nitric oxide)
• II. PLASMA-DERIVED MEDIATORS (PLASMA PROTEASES)

Products of:
1. The kinin system
2. The clotting system
3. The fibrinolytic system
4. The complement system
1. Vasoactive amines
(Histamine, 5-hydroxytryptamine, neuropeptides)
Early inflammatory response
Histamine
• It is stored in the granules of mast cells, basophils and platelets.
• Released when
 Stimuli or substances inducing acute inflammation
 Anaphylatoxins like fragments of complement C3a, and C5a,
 Histamine-releasing factors from neutrophils, monocytes and platelets.
 Interleukins.
• vasodilatation,
• increased vascular (venular) permeability,
• itching
• Pain
• Products of arachidonic acid metabolism
5-hydroxytryptamine
• It is present in tissues like chromaffin cells of GIT, spleen, nervous
tissue, mast cells and platelets.
• similar to histamine but it is a less potent mediator of increased
vascular permeability and vasodilatation than histamine
Neuropeptides
• tachykinin neuropeptides, such as substance P, neurokinin A,
vasoactive intestinal polypeptide (VIP) and somatostatin.
• produced in the central and peripheral nervous systems.
The major proinflammatory actions of these neuropeptides
is as follows:
a) Increased vascular permeability.
b) Transmission of pain stimuli.
c) Mast cell degranulation.
2. Arachidonic acid metabolites (Eicosanoids)
• i. Metabolites via cyclo-oxygenase pathway
• (prostaglandins, thromboxane A2, prostacyclin, resolvins)
• ii. Metabolites via lipo-oxygenase pathway
• (5-HETE, leukotrienes, lipoxins)
Arachidonic acid is a constituent of the phospholipid cell
membrane

Eicosanides are released from either one two pathways

 Metabolites via cyclo-oxygenase pathway

(prostaglandins, thromboxane A2, prostacyclin, resolvins)

They are also called as Autocoids (local hormones; act nearby)

a) Prostaglandins (PGD2, PGE2 and PGF2-α). PGD2 and PGE2
• increased venular permeability,
• vasodilatation and bronchodilatation and inhibit inflammatory cell
function.
• PGF2-α – vasodilatation and bronchoconstriction.
b) Thromboxane A2 (TXA2)
• active in platelet aggregation,
• vasoconstrictor and broncho-constrictor.
• c) Prostacyclin (PGI2). PGI2 induces vasodilatation,
bronchodilatation and inhibits platelet aggregation.
• d) Resolvins inhibiting production of pro-inflammatory cytokines.

• Drugs such as NSAIDs and COX-2 Inhibitors inhibit the COX

activity
Metabolites via lipo-oxygenase pathway
5-HETE, leukotrienes, lipoxins.
Lipooxygenase present in neutrophils act on Arachidonic acid to form
5-HETE (5-hydroxy eicasa tetraenoic acid)an intermediate product, is a potent
chemotactic agent for neutrophils.
b) Leukotrienes (LT)
smooth muscle contraction and thereby induce vasoconstriction,
bronchoconstriction and increased vascular permeability; hence they are also
called as slow reacting substances of anaphylaxis (SRS-As).
c) Lipoxins (LX) Lipooxygenase-12 present in platelets acts on LTA4 derived from
neutrophils and forms LXA4 and LXB4. Lipoxins act to regulate and
counterbalance actions of leukotrienes
• Lysosomal Component

3. LYSOSOMAL COMPONENTS.
• The inflammatory cells neutrophils and monocytes, contain lysosomal granules which on
release produces a variety of mediators of inflammation.

Which are as follows.

• Granules of neutrophils: there are 3 types of granules primary or azurophil, secondary or specific
and tertiary.
• Primary or azurophil granules are large and contain functionally active enzymes. These are
myeloperoxidase, acid hydrolase, acid phosphatase, lysozyme, defensin, phospholipase,
cathepsinG, elastase and protease.
b) Secondary or specific granules: contain alkaline phosphatase, lactoferrin, gelatinase,
collginase, lysozyme, Vit B12 binding proteins, plasminogen activator.
c)Tertiary granules or C particles contain gelatinses and acid hydrolases.
2)Granules of monocytes and tissue macrophages: these cells on degranulation release
mediators of inflammation like acid proteases, collagense, elastase and plasminogen activator.
 They are more active in chronic inflammation than acute inflammation.
4.PLATELET ACTIVATING FACTOR :
 It is released from IgE sensitised basophils or mast cells, other leucocytes, endothelium and
platelets. Its action is the aggregation platelet.
The actions PAF as a mediator of inflammation are:
 increased vascular permeability,
 vasodilatation in low conc. and vasoconstriction otherwise,
 Broncho-constriction,
 adhesion of leucocytes to endothelium,
 Chemotaxis of platelets.
5.CYTOKINES: are the polypeptide substances produced by activated lymphocytes and
activated monocytes (monokines).
 These agents may act on own cells producing them or and on other cells. There are over 200
cytokines are been described, but the major cytokines are IL1, TNFα and β, IFNγ and IL8 and
PF4.

 IL1 and TNF alpha are formed by activated macrophages while TNF beta and IFN gamma are
produced by activated T cells.

 The chemokines include interleukin 8(released from activated macrophages) and platelet
factor 4 from activated platelets, both of which are potent chemo attractant for inflammatory
cells and hence their name.
5. Cytokines
• Cytokines are polypeptide substances produced
• activated lymphocytes (lymphokines) and activated monocytes (monokines).
• may act on ‘self’ cells or other cells producing them or on other cells

• Major cytokins:
• interleukin-1 (IL-1), tumour necrosis factor (TNF)-α – released by Activated macrophages
• interferon (IFN)-γ, TNF-β – released by activated T-cells
• chemokines (IL-8, PF-4) – released by chemokines
• Actions of Cytokines
I. IL-1 and TNF-α, TNF-β - ncreased leucocyte adherence, thrombogenicity, elaboration of
other cytokines, fibroblastic proliferation and acute phase reactions.
II. IFN-γ - activation of macrophages and neutrophils, ynthesis of nitric acid synthase.
III. Chemokines are a family of chemoattractants for inflammatory cells
• 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, nitric oxide)
• Oxygen-derived metabolites are released from activated neutrophils and macrophages and
include superoxide oxygen (O’2), H2O2, OH’ and toxic NO products.
• These oxygen-derived free radicals have the following action in inflammation:
• Endothelial cell damage and thereby increased vascular permeability.
• Activation of protease and inactivation of antiprotease
• causing tissue matrix damage.
• Damage to other cells.

• Nitric oxide (NO) formed by activated macrophages

• NO plays the following role in mediating inflammation:
• Vasodilatation
• Anti-platelet activating agent
• Possibly microbicidal action.
 PLASMA-DERIVED MEDIATORS (PLASMA
PROTEASES)
• These include the various products derived from 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.

activation of clotting, fibrinolytic and kinin systems.

• The Kinin System
• XIIa

Kallekrein Kallekrein act on high

By plasma prelallekrein by molecular weight
Factor XIIA
the action of pre-kallekrein kininogen to form
activator bradykinin
• Bradykinin acts in the early stage of inflammation
• smooth muscle contraction;
• vasodilatation;
• increased vascular permeability; and
• pain.

Plasmin
• 2. The Clotting System

XII A Fibrinogen Fibrin +

fibrinopeptides
Fibrinopeptide

• increases vascular permeability

• chemotaxis for leucocyte
• anticoagulant activity
 • The Fibrinolytic System

Kallikrein Release Activate

Endothelial Plasminogen Plasminogen to
Cells Activator form plasmin
Leukocytes
• The actions of plasmin in inflammation

• activation of factor XII to form prekallikrein activator to generate bradykinin

• splits off complement C3 to form C3a – permeability factor
• degrades fibrin to form fibrin split products to increase vascular permeability and are
chemotactic to leucocytes.
• The Complement System
•
• Stimulated by -
 classic pathway (antigen – antibody complexes
 alternate pathway (non-immunologic agents such as bacterial toxins, cobra venoms
and IgA}

which release
• anaphylatoxins (C3a, C4a and C5a),
• membrane attack complex (MAC) i.e. C5b,C6,7,8,9.
• C3a, C5a, C4a (anaphylatoxins) - release of histamine, cause increased vascular permeability
causing oedema in tissues, augments phagocytosis.
• C3b is an opsonin.
• C5a is chemotactic for leucocytes.
• Membrane attack complex (MAC) (C5b-C9) causes holes in the phospholipid
membrane of the cell.
 THE INFLAMMATORY CELLS

• The cells participating in acute and chronic inflammation are circulating leucocytes, plasma cells
and tissue macrophages
• Summary of morphology, characteristics and functions will be described
1. Polymorphonuclear Neutrophils (PMNs)
2. Eosinophils
3. Basophils (Mast Cells)
4. Lymphocytes
5. Plasma Cells
6. Mononuclear-Phagocyte System (Reticuloendothelial System)
7. Giant Cells
1. Polymorphonuclear Neutrophils (PMNs)
• neutrophils or polymorphs, basophils and eosinophils are known as granulocytes due to the
presence of granules in the cytoplasm.
• Granules contain proteases, myeloperoxidase, lysozyme, esterase, aryl sulfatase, acid and
alkaline phosphatase, and cationic proteins.
• Comprise of 40-75% of circulating leucocytes
• Increased in infections
• Arise in bone marrow in the stem cells
The functions of neutrophils in inflammation:
i) Initial phagocytosis of microorganisms
• adhesion of neutrophils to vascular endothelium
• emigration through the vessel wall
• Chemotaxis
• Engulfment
• Degranulation
ii) Engulfment of antigen-antibody complexes and non-microbial material
iii) Harmful effect - basement membrane destruction of the glomeruli and small blood
vessels
2. Eosinophils
• larger than neutrophils but fewer in number
• comprising 1 to 6% of total blood leucocytes
• Similar to neutrophils
• granules of eosinophils are richer in myeloperoxidase than neutrophils and lack lysozyme.
• They are also rich in major basic protein and eosinophil cationic protein which have bactericidal
and toxic action against helminthic parasites
• High level of steroid hormones leads to fall in number of eosinophils and even disappearance from
blood
3. Basophils (Mast Cells)
The basophils comprise about 1% of circulating leucocytes and are morphologically and
pharmacologically similar to mast cells of tissue.
• The granules of basophils are laden with heparin and histamine.
• Basophils and mast cells have receptors for IgE and degranulate when cross-linked with antigen.

The role of these cells in inflammation are:

i) in immediate and delayed type of hypersensitivity reactions; and
ii) release of histamine by IgE-sensitised basophils.
4. Lymphocytes
• these cells are the most numerous of the circulating leucocytes (20-45%)
• They are present in spleen, thymus, lymph nodes and mucosa-associated lymphoid tissue (MALT)
apart from blood
• Their role in antibody formation (B lymphocytes) and in cell-mediated immunity (T lymphocytes)

Functions:
• role in antibody formation (B lymphocytes) and in cell-mediated immunity (T lymphocytes)
• In tissues, they are dominant cells in chronic inflammation and late stage of acute inflammation.
• 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
• They develop from B lymphocytes and are rich in RNA and γ-globulin in their cytoplasm
• These cells are most active in antibody synthesis.
Their number is increased in
i) prolonged infection with immunological responses e.g. in syphilis, rheumatoid arthritis,
tuberculosis;
ii) hypersensitivity states; and
iii) multiple myeloma.
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:
The mononuclear phagocytes are the scavenger cells of the body as well as participate in immune
system of the body
Role of macrophages in inflammation
i) Phagocytosis (cell eating) and pinocytosis (cell drinking).
• ii) Macrophages on activation by lymphokines released by T lymphocytes or by non-
immunologic stimuli elaborate a variety of biologically active substances as under
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
• cells of the monocyte/macrophage lineage are capable of fusion to form multinucleated giant cells
(MGCs)
• in chronic inflammation when the macrophages fail to deal with particles to be removed, they fuse
together and form multinucleated giant cells.
Some of the common types of giant cells are
A. Giant cells in inflammation
i) Foreign body giant cells. These are seen in chronic infective granulomas, leprosy and
tuberculosis
• ii) Langhans’ giant cells. These are seen in tuberculosis and sarcoidosis.
iii) Touton giant cells. These multinucleated cells have vacuolated cytoplasm due to lipid content e.g. in
xanthoma.
iv) Aschoff giant cells. These multinucleate giant cells are derived from cardiac histiocytes and are seen in
rheumatic nodule
B. Giant cells in tumours
i. Anaplastic cancer giant cells: These giant cells are not derived from macrophages but are formed
from dividing nuclei of the neoplastic cells e.g. carcinoma of the liver, various soft tissue sarcomas
etc.
ii) Reed-Sternberg cells. These are also malignant tumour giant cells which are generally binucleate and
are seen in various histologic types of Hodgkin’s lymphomas.
iii) Giant cell tumour of bone. This tumour of the bones has uniform distribution of osteoclastic giant
cells spread in the stroma.
 FACTORS DETERMINING VARIATION IN
INFLAMMATORY RESPONSE
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;
ii) Virulence. Many species and strains of organisms may have varying virulence e.g. the three
strains of C. diphtheriae (gravis, intermedius and mitis) produce the same diphtheria exotoxin but
in different amount.
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 dministered 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
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

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:
Serus: 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.
 MORPHOLOGY OF INFLAMMATION

Inflammation – it is –
• e.g. appendicitis, hepatitis, cholecystitis, meningitis etc.
1. PSEUDOMEMBRANOUS INFLAMMATION
• It is inflammatory response of mucous surface (oral, respiratory, bowel) to toxins of diphtheria or
irritant gases.
• denudation of epithelium - plasma exudes on the surface – coagulates - together with necrosed
epithelium, forms false membrane
2. ULCER. local defects on the surface of an organ produced by inflammation
Common sites for ulcerations
• 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).
• 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 purulent exudate or pus and the process
of abscess formation is known as suppuration. The bacteria which cause suppuration are called
pyogenic
• 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.
Eg:
i) Boil or furuncle - inflammation via hair follicles in the dermal tissue
ii) Carbuncle - 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.
i) Bacteraemia - presence of small number of bacteria in the blood which do not multiply significantly.
ii) Septicaemia : presence of rapidly multiplying, highly pathogenic bacteria in the blood e.g.
pyogenic cocci, bacilli of plague etc.
Accompanied by toxaemia, multiple small haemorrhages, neutrophilic leucocytosis and
disseminated intravascular coagulation (DIC).
iii) Pyaemia
dissemination of small septic thrombi in the blood which cause their effects at the site where they
are lodged.
a) Pyaemic abscesses
b) Septic infarcts
 SYSTEMIC EFFECTS OF ACUTE
INFLAMMATION
fever, leucocytosis and lymphangitis
1. Fever – due to release of prostaglandins, interleukin-1 and TNF-α in response to infection.
2. Leucocytosis: usually in the range of 15,000- 20,000/μl.
Bacterial infections : Neutrophilia
viral infections : lymphocytosis
parasitic infestations : Eosinophilia :
Typhoid fever : leucopenia with relative lymphocytosis.
3. Lymphangitis-lymphadenitis
The lymphatics and lymph nodes that drain the inflamed tissue show reactive inflammatory changes
in the form of lymphangitis and lymphadenitis
4. Shock may occur in severe cases.
Massive release of cytokine TNF-α; results in profuse systemic vasodilatation, increased vascular
permeability and intravascular volume loss.
Results in hypotension and shock
Systemic activation of coagulation pathway may occur leading to microthrombi throughout the body
and result in disseminated intravascular coagulation (DIC), bleeding and death
 FATE OF ACUTE INFLAMMATION

1. Resolution
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.
3. Suppuration. When the pyogenic bacteria causing acute inflammation result in severe tissue
necrosis, the process progresses to suppuration.
• intense neutrophilic infiltration
• mixture of neutrophils, bacteria, fragments of necrotic tissue, cell debris and fibrin
= pus = containing in a cavity = abcess
Abcess – turn into dense fibrous tissue – calcification
4. Chronic inflammation.
Persisting or recurrent acute inflammation
may progress to chronic inflammation
processes of inflammation and healing proceed side by side.
 REGULATORS OF INFLAMMATION

• Inflammatory cell can cause damage

• Kept in check by host regulatory mechanisms
I. Acute Phase Reactants – many APR proteins are released in plasma in response to tissue
trauma and infection. They protect the from harmful effects of toxic molecules generated in
inflammation.
Certain Cellular protection factors
Coagulation proteins
Transport proteins
Immune Agents
Stress Proteins
Antioxidants
ii) Glucosteroids – their levels are raised in infection and trauma
iii) Free Cytokine receptors –
IV) Anti-inflammatory chemical mediators PGE2 or prostacyclin have pro-inflammatory and anti-
inflammatory actions
 CHRONIC INFLAMMATION
Prolonged process in which tissue destruction and inflammation occur at the same time.
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
When repeated bouts of acute inflammation culminate in 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.
Features of Chronic Inflammation
• Mononuclear Cell Infiltration:
• The site of chronic inflammatory lesion may be infiltrated by mononuclear
inflammatory cells - phagocytes and lymphoid cells
• Phagocytes are - circulating monocytes, tissue macrophages, epithelioid cells

• Macrophages are deposited at the site by chemotactic factors, local proliferators

• On activation, macrophages release several biologically active substances e.g.
acid and neutral proteases, oxygen-derived reactive metabolites and cytokines.
• Other chronic inflammatory cells include lymphocytes, plasma cells, eosinophils
and mast cells.
Tissue Destruction and Necrosis
macrophages 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.
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

1. Fever. Invariably there is mild fever, often with loss of weight and weakness.
• Elevation of temperature – 1 to 4 degrees; in response to pyrogens which stimulate prostaglandin synthesis
• In hypothalamus prostaglandins stimulate production of prostaglandins - reset the temperature to higher level
• NSAIDs work by inhibiting the production of prostaglandins
• Fever may induce heat shock proteinwhich enhance lymphocyte response to microbial agents
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. Increase in plasma proteins, C-reactive protein,
fibrinogen and serum amyloid A protein; rise in fibrinogen causes RBCs to forms stacks
5. Amyloidosis. Long-term cases of chronic suppurative inflammation may develop secondary systemic (AA)
amyloidosis.
Types of Chronic Inflammation
1. Chronic non-specific inflammation. It is characterised by non-specific inflammatory cell infiltration
e.g. chronic osteomyelitis, lung abscess.
A variant of this type of chronic inflammatory response is chronic suppurative inflammation in which
infiltration by polymorphs and abscess formation are additional features e.g. actinomycosis.
2. Chronic granulomatous inflammation.
by formation of granulomas
e.g. tuberculosis, leprosy, syphilis, actinomycosis, sarcoidosis etc.
Granuloma - circumscribed, tiny lesion, composed predominantly of collection of
modified macrophages called epithelioid cells, and rimmed at the periphery by lymphoid cells.
 HEALING

Healing is the body response to injury in an attempt to restore normal structure and function.
Healing involves 2 distinct processes:
Regeneration when healing takes place by proliferation of parenchymal cells and usually results in
complete restoration of the original tissues.
Repair when healing takes place by proliferation of connective tissue elements resulting in fibrosis
and scarring.
At times, both the processes take place simultaneously
Regeneration
Labile Cell:
• These cells continue to multiply throughout life under normal physiologic conditions
alimentary tract, respiratory tract, urinary tract, vagina, cervix, uterin endometrium, haematopoietic cells of bone
marrow and cells of lymph nodes and spleen.
Stable cells:
• These cells decrease or lose their ability to proliferate after adolescence but retain the capacity to multiply in
response to stimuli throughout adult life.
• parenchymal cells of organs like liver, pancreas, kidneys, adrenal and thyroid; mesenchymal cells like smooth
muscle cells, fibroblasts, vascular endothelium, bone and cartilage cells.
Permanent cells.
• These cells lose their ability to proliferate around the time of birth.
• These cells lose their ability to proliferate around the time of birth. neurons of nervous system, skeletal muscle
and cardiac muscle cells.
• 1. Labile cells which are continuously dividing cells remain
• in the cell cycle from one mitosis to the next.
• 2. Stable cells are in the resting phase (G0) but can be stimulated
• to enter the cell cycle.
• 3. Permanent cells are non-dividing cells which have left
• the cell cycle and die after injury.
• Regeneration of any type of parenchymal cells involves the following 2 processes:

i. Proliferation of original cells from the margin of injury with migration so as to cover the gap.
ii. Proliferation of migrated cells with subsequent differentiation and maturation so as to
reconstitute the original tissue.
 REPAIR

Repair is the replacement of injured tissue by fibrous tissue.

Two processes are involved in repair:
1. Granulation tissue formation
2. Contraction of wounds
Repair response takes place by participation of
• mesenchymal cells (consisting of connective tissue stem cells, fibrocytes and histiocytes),
endothelial cells, macrophages, platelets, and the parenchymal cells of the injured organ.
 1. GRANULATION TISSUE FORMATION

• Pink appearance
• Each granulocyte – new blood vessel (slightly lifted)

A new connective tissue and microscopic blood vessels that form on the surfaces of a wound
during the healing process. Granulation tissue typically grows from the base of a wound and is able
to fill wounds of almost any size.
3 phases in the formation of granulation tissue
1. PHASE OF INFLAMMATION. Following injury. Acute inflammatory response with
exudation of plasma, neutrophils and some 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
• fibrogenesis.
Angiogenesis
Proliferation of endothelial cells from the margins of severed blood vessels. Soon, these blood
vessels differentiate into muscular arterioles, thin-walled venules and true capillaries.
The process of angiogenesis is stimulated with proteolytic destruction of basement membrane.
Angiogenesis takes place under the influence of following factors:
a) Vascular endothelial growth factor (VEGF)
b) Platelet-derived growth factor (PDGF)
Fibrogenesis
Fibroblasts originate from fibrocytes or division of fibroblasts. (myofibroblasts) Collagen fibrils
begin to appear by 6th day. More collagen is formed resulting in the formation of cicatrisation
(inactive looking scar)
 2. CONTRACTION OF WOUNDS

• The wound starts contracting after 2-3 days is completed by the 14th day.
• The wound is reduced by approximately 80% of its original size. Contracted wound results in
rapid healing
 TYPES OF WOUND HEALING

• Wound healing can be accomplished in one of the following two ways:

• Healing by first intention (primary union)

• Healing by second intention (secondary union).
 HEALING BY FIRST INTENTION (PRIMARY
UNION)
I. clean and uninfected;
II. surgically incised;
III. without much loss of cells and tissue; and
IV. edges of wound are approximated by surgical sutures.
 THE SEQUENCE OF EVENTS

1.Initial haemorrhage
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. within 24 hours with appearance of polymorphs from the
margins of incision. By 3rd day, polymorphs are replaced by macrophages.
3.Epithelial changes: cells of epidermis migrate towards incisional space. The wound is covered
within 48 hours. By 5th day multi-layered new epidermis is formed which is differentiated into
superficial and deeper cells.
4.Organisation – by 3rd day fibroblasts invade the injured area
5th day – collagen fibrils start forming
4th week - scar tissue formed which contains cellular and vascular elements, few
inflammatory cells and epetheliased surface.
5. Suture tracts: each suture track is a separate wound and incites the same phenomena as
healing by primary intension.
A. Suture track and wound are filled with blood clot and inflammatory response is seen around the margins
B. Spurs of epidermal cells migrate along the incised margin and around the suture tract
C. Removal of suture around 7th day results in scar tissue at the site of incision and suture tract
 HEALING BY SECONDARY INTENTION

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.
Events are similar to primary union but have larger tissue defects which has to be bridged.
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 Epithelial spurs from the margins of wound meet in the middle to cover the
gap and separate the underlying viable tissue from necrotic tissue at the surface forming scab.
4. Granulation tissue Granulation tissue is formed by proliferation of fibroblasts and
neovascularisation from the adjoining viable elements. The newly-formed granulation tissue is
deep red, granular and very fragile.
5.Wound Contraction Due to the action of myofibroblasts present in granulation tissue, the
wound contracts to one-third to one fourth of its original size.
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.
 A. The open wound is filled with blood clot and there is inflammatory response at the junction
B. Epethelial cells from the margin separate the underlying viable tissue from necrotic tissue at the surface forming scab.
C. After contraction of the wound, a scar smaller than the original wound is left.
 FACTORS INFLUENCING WOUND HEALING

A. Local Factors:
 Infection
 Poor blood supply
 Foreign bodies
 Movement
 Exposure to ionising radiation
 Type size and location
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, vitaminC (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. Haematologic abnormalities like defect of neutrophil functions (chemotaxis and phagocytosis),
and neutropenia and bleeding disorders slow the process of wound healing