INFLAMMATION

INTRODUCTION
Definition: Inflammation is a local response (reaction) of living vascularized tissues to
endogenous and exogenous stimuli. The term is derived from the Latin "inflammare"
meaning to burn. Inflammation is fundamentally destined to localize and eliminate the
causative agent and to limit tissue injury.

Thus, inflammation is a physiologic (protective) response to injury, an observation made by

Sir John Hunter in 1794 concluded: “inflammation is itself not to be considered as a disease
but as a salutary operation consequent either to some violence or to some diseases”.

Causes:

Causes of inflammation are apparently causes of diseases such as

 Physical agents - mechanical injuries, alteration in temperatures and pressure,
radiation injuries.
 Chemical agents- including the ever increasing lists of drugs and toxins.
 Biologic agents (infectious) - bacteria, viruses, fungi, parasites
 Immunologic disorders- hypersensitivity reactions, autoimmunity,
immunodeficiency states.
 Genetic/metabolic disorders- examples gout, diabetes mellitus

Nomenclature: The nomenclatures of inflammatory lesion are usually indicated by the suffix
'itis'. Thus, inflammation of the appendix is called appendicitis and that of meninges as
meningitis. However, like any rule, it has its own exceptions examples pneumonia.

Classification:

Inflammation is classified crudely based on duration of the lesion and histologic appearances
into acute and chronic inflammation.

ACUTE INFLAMMATION
Acute inflammation is an immediate and early response to an injurious agent and it is
relatively of short duration, lasting for minutes, several hours or few days.

It is characterized by exudation of fluids and plasma proteins and the emigration of

predominantly neutrophilic leucocytes to the site of injury.

The five cardinal signs of acute inflammation are

 Redness (rubor) which is due to dilation of small blood vessels within damaged
tissue as it occurs in cellulitis.
 Heat (calor) which results from increased blood flow (hyperemia) due to regional
vascular dilation
 Swelling (tumor) which is due to accumulation of fluid in the extravascular space
which, in turn, is due to increased vascular permeability.
  Pain (dolor), which partly results from the stretching & destruction of tissues due to
inflammatory edema and in part from pus under pressure in as abscess cavity. Some
chemicals of acute inflammation, including bradykinins, prostaglandins and serotonin
are also known to induce pain.
 Loss of function: The inflammed area is inhibited by pain while severe swelling may
also physically immobilize the tissue.

Events of acute inflammation:

Acute inflammation is categorized into an early vascular and a late cellular responses.

 The Vascular response has the following steps:

a) Immediate (momentary) vasoconstriction in seconds due to neurogenic or chemical
stimuli.
b) Vasodilatation of arterioles and venules resulting in increased blood flow.
c) After the phase of increased blood flow there is a slowing of blood flow & stasis due
to increased vascular permeability that is most remarkably seen in the post-capillary
venules. The increased vascular permeability oozes protein-rich fluid into
extravascular tissues. Due to this, the already dilated blood vessels are now packed
with red blood cells resulting in stasis. The protein-rich fluid which is now found in the
extravascular space is called exudate. The presence of the exudates clinically
appears as swelling. Chemical mediators mediate the vascular events of acute
inflammation.
 The Cellular response

The cellular response has the following stages:

1. Migration, rolling, pavementing, & adhesion of leukocytes

2. Transmigration of leukocytes
3. Chemotaxis
4. Phagocytosis

Normally blood cells particularly erythrocytes in venules are confined to the central (axial)
zone and plasma assumes the peripheral zone. As a result of increased vascular
permeability (See vascular events above), more and more neutrophils accumulate along the
endothelial surfaces (peripheral zone).

A) Margination, rolling, pavementing, and adhesion of leukocytes

 Margination is a peripheral positioning of white cells along the endothelial cells.

 Subsequently, rows of leukocytes tumble slowly along the endothelium in a process
known as rolling
 In time, the endothelium can be virtually lined by white cells. This appearance is
called pavementing.
 Thereafter, the binding of leukocytes with endothelial cells is facilitated by cell
adhesion molecules such as selectins, immunoglobulins, integrins, etc which result in
adhesion of leukocytes with the endothelium.

B). Transmigration of leukocytes

  Leukocytes escape from venules and small veins but only occasionally from
capillaries. The movement of leukocytes by extending pseudopodia through the
vascular wall occurs by a process called diapedesis.
 The most important mechanism of leukocyte emigration is via widening of inter-
endothelial junctions after endothelial cells contractions. The basement membrane is
disrupted and resealed thereafter immediately.

C). Chemotaxis:

 A unidirectional attraction of leukocytes from vascular channels towards the site of

inflammation within the tissue space guided by chemical gradients (including bacteria
and cellular debris) is called chemotaxis.
 The most important chemotactic factors for neutrophils are components of the
complement system (C5a), bacterial and mitochondrial products of arachidonic acid
metabolism such as leukotriene B4 and cytokines (IL-8). All granulocytes, monocytes
and to lesser extent lymphocytes respond to chemotactic stimuli.
 How do leukocytes "see" or "smell" the chemotactic agent? This is because
receptors on cell membrane of the leukocytes react with the chemoattractants
resulting in the activation of phospholipase C that ultimately leads to release of
cytosolic calcium ions and these ions trigger cell movement towards the stimulus.

D) Phagocytosis

 Phagocytosis is the process of engulfment and internalization by specialized cells of

particulate material, which includes invading microorganisms, damaged cells, and
tissue debris.
 These phagocytic cells include polymorphonuclear leukocytes (particularly
neutrophils), monocytes and tissue macrophages.

Phagocytosis involves three distinct but interrelated steps.

1). Recognition and attachment of the particle to be ingested by the leukocytes:

Phagocytosis is enhanced if the material to be phagocytosed is coated with certain plasma

proteins called opsonins. These opsonins promote the adhesion between the particulate
material and the phagocyte’s cell membrane. The three major opsonins are: the Fc fragment
of the immunoglobulin, components of the complement system

C3b and C3bi, and the carbohydrate-binding proteins – lectins.

Thus, IgG binds to receptors for the Fc piece of the immunoglobulin (FcR) whereas

3cb and 3bi are ligands for complement receptors CR1 and CR2 respectively.

2). Engulfment: During engulfment, extension of the cytoplasm (pseudopods) flow around
the object to be engulfed, eventually resulting in complete enclosure of the particle within the
phagosome created by the cytoplasmic membrane of the phagocytic cell.
As a result of fusion between the phagosome and lysosome, a phagolysosome is formed
and the engulfed particle is exposed to the degradative lysosomal enzymes.

3) Killing or degradation

The ultimate step in phagocytosis of bacteria is killing and degradation. There are two forms
of bacterial killing

a). Oxygen-independent mechanism:

 This is mediate by some of the constituents of the primary and secondary granules
of polymorphonuclear leukocytes. These include:
o Bactericidal permeability increasing protein (BPI)
o Lysozymes
o Lactoferrin
o Major basic protein
o Defensins
 It is probable that bacterial killing by lysosomal enzymes is inefficient and relatively
unimportant compared with the oxygen dependent mechanisms. The lysosomal
enzymes are, however, essential for the degradation of dead organisms within
phagosomes.

b) Oxygen-dependent mechanism:

There are two types of oxygen- dependent killing mechanisms

i) Non-myeloperoxidase dependent

 The oxygen - dependent killing of microorganisms is due to formation of reactive

oxygen species such as hydrogen peroxide (H2O2), super oxide (O2) and hydroxyl
ion (HO-) and possibly single oxygen (1O2). These species have single unpaired
electrons in their outer orbits that react with molecules in cell membrane or nucleus
to cause damages. The destructive effects of H2O2 in the body are gauged by the
action of the glutathione peroxidase and catalase.

ii) Myloperoxidase–dependent

 The bactericidal activity of H2O2 involves the lysosomal enzyme myeloperoxidase,

which in the presence of halide ions converts H2O2 to hypochlorous acid (HOCI).
This H2O2 – halide - myeloperoxidase system is the most efficient bactericidal
system in neutrophils. A similar mechanism is also effective against fungi, viruses,
protozoa and helminths.

Like the vascular events, the cellular events (i.e. the adhesion, the transmigration, the
chemotaxis, & the phagocytosis) are initiated or activated by chemical mediators.

Chemical mediators of inflammation

Chemical mediators account for the events of inflammation. Inflammation has the following
sequence:

Cell injury -> Chemical mediators -> Acute inflammation (i.e. the vascular & cellular events).

Sources of mediators:

The chemical mediators of inflammation can be derived from plasma or cells.

a) Plasma-derived mediators:

i) Complement activation

 increases vascular permeability (C3a,C5a)

 activates chemotaxis (C5a)
 opsoninization (C3b,C3bi)

ii) Factor XII (Hegman factor) activation

Its activation results in recruitment of four systems: the kinin, the clotting, the fibrinolytic and
the compliment systems.

b) Cell-derived chemical mediatos:

Cell-derived chemical mediators include:

Cellular mediators Cells of origin Function
Histamine Mast cells, basophils vascular leakage & platelets
Serotonine Platelets Vascular leakage
Lysosomal enzymes Neutrophils Bacterial & tissue
destruction, macrophages
Prostaglandins All leukocytes Vasodilatation, pain, fever
Leukotrienes All leukocyte, Broncho and
Chemoattractant, LB4, LC4, vasoconstriction
LCD4, & LE4
Platelet activating factor All leukocytes Bronchoconstriction and
WBC priming
Activated oxygen species All leukocytes Endothelial and tissue
damage
Cytokines Lymphocytes, macrophages Leukocyte activation
Nitric oxide Macrophages Leukocyte activation

 Most mediators perform their biologic activities by initially binding to specific

receptors on target cells. Once activated and released from the cells, most of these
mediators are short lived. Most mediators have the potential to cause harmful effects.

Morphology of acute inflammation

 Characteristically, the acute inflammatory response involves production of exudates.

An exudate is an oedema fluid with high protein concentration, which frequently
contains inflammatory cells.
  A transudate is simply a non-inflammatory oedema caused by cardiac, renal,
nutritional, & other disorders.

The differences between an exudate and a transudate are summarised below

EXUDATE TRANSUDATE
Cause Acute inflammation Non-inflammatory
disorders
Appearance Coloured, turbid, haemorrhagic Clear, translucent or pale
yellow
Specific gravity Greater than or equal to 1.020 Much less
Spontaneous Yes No
coagulability
Protein content >3mg/dl Insignificant
Cells Abundant WBC, RBC & Cell debris Only few mesothelial cells
usually present
Bacteria Present Absent

There are different morphologic types of acute inflammation:

1) Serous inflammation

 This is characterized by an outpouring of a thin fluid that is derived from either the
blood serum or secretion of mesothelial cells lining the peritoneal, pleural, and
pericardial cavities.
 It resolves without reactions

2) Fibrinous inflammation

 More severe injuries result in greater vascular permeability that ultimately leads to
exudation of larger molecules such as fibrinogens through the vascular barrier.
 Fibrinous exudate is characteristic of inflammation in serous body cavities such as
the pericardium (butter and bread appearance) and pleura.
 Course of fibrinous inflammation include:
o Resolution by fibrinolysis
o Scar formation between parietal and visceral surfaces i.e. the exudates get
organized
o Fibrous strand formation that bridges the pericardial space.

3) Suppurative (Purulent) inflammation

This type of inflammation is characterized by the production of a large amount of pus. Pus is
a thick creamy liquid, yellowish or blood stained in colour and composed of

 A large number of living or dead leukocytes (pus cells)

 Necrotic tissue debris
 Living and dead bacteria
 Oedema fluid

There are two types of suppurative inflammation:

A) Abscess formation:

 An abscess is a circumscribed accumulation of pus in a living tissue. It is

encapsulated by a so-called pyogenic membrane, which consists of layers of fibrin,
inflammatory cells and granulation tissue.

B) Acute diffuse (phlegmonous) inflammation

 This is characterized by diffuse spread of the exudate through tissue spaces. It is

caused by virulent bacteria (eg. streptococci) without either localization or marked
pus formation. Example: Cellulitis (in palmar spaces).

4) Catarrhal inflammation

 This is a mild and superficial inflammation of the mucous membrane. It is commonly

seen in the upper respiratory tract following viral infections where mucous secreting
glands are present in large numbers, eg. Rhinitis.

5) Pseudomembranous inflammation

 The basic elements of pseudomembranous inflammation are extensive confluent

necrosis of the surface epithelium of an inflamed mucosa and severe acute
inflammation of the underlying tissues. The fibrinogens in the inflamed tissue
coagulate within the necrotic epithelium. And the fibrinogen, the necrotic epithelium,
the neutrophilic polymorphs, red blood cells, bacteria and tissue debris form a false
(pseudo) membrane which forms a white or coloured layer over the surface of
inflamed mucosa.
 Pseudomembranous inflammation is exemplified by Dipthetric infection of the
pharynx or larynx and Clostridium difficille infection in the large bowel following
certain antibiotic use.

Effects of acute inflammation:

A. Beneficial effects

 Dilution of toxins: The concentration of chemical and bacterial toxins at the site of
inflammation is reduced by dilution in the exudate and its removal from the site by the
flow of exudates from the venules through the tissue to the lymphatics.
 Protective antibodies: Exudation results in the presence of plasma proteins
including antibodies at the site of inflammation. Thus, antibodies directed against the
causative organisms will react and promote microbial destruction by phagocytosis or
complement-mediated cell lysis.
 Fibrin formation: This prevents bacterial spread and enhances phagocytosis by
leukocytes.
 Plasma mediator systems provisions: The complement, coagulation, fibrinolytic, &
kinin systems are provided to the area of injury by the process of inflammation.
 Cell nutrition: The flow of inflammatory exudates brings with it glucose, oxygen and
other nutrients to meet the metabolic requirements of the greatly increased number
of cells. It also removes their solute waste products via lymphatic channels.
  Promotion of immunity: Micro-organisms and their toxins are carried by the
exudates, either free or in phagocytes, along the lymphatics to local lymph nodes
where they stimulate an immune response with the generation of antibodies and
cellular immune mechanisms of defence.

B. Harmful effects

 Tissue destruction Inflammation may result in tissue necrosis and the tissue
necrosis may, in turn, incite inflammation.
 Swelling: The swelling caused by inflammation may have serious mechanical effects
at certain locations. Examples include acute epiglottitis with interference in breathing;
acute meningitis and encephalitis with effects of increased intracranial pressure.
 Inappropriate response: The inflammatory seen in hypersensitivity reactions is
inappropriate (i.e. exaggerated).

Course of acute inflammation

Acute inflammation may end up in:

 Resolution: i.e. complete restitution of normal structure and function of the tissue,
e.g. lobar pneumonia.
 Healing by fibrosis (scar formation).
 Chronic inflammation.

CHRONIC INFLAMMATION
Definition: Chronic inflammation can be defined as a prolonged inflammatory process
(weeks or months) where an active inflammation, tissue destruction and attempts at repair
are proceeding simultaneously.

Causes of chronic inflammation:

1. Persistent infections

 Certain microorganisms associated with intracellular infection such as tuberculosis,

leprosy, certain fungi etc characteristically cause chronic inflammation.
 These organisms are of low toxicity and evoke delayed hypersensitivity reactions.

2. Prolonged exposure to nondegradable but partially toxic substances either

endogenous lipid components which result in atherosclerosis or exogenous substances such
as silica, asbestos.

3. Progression from acute inflammation: Acute inflammation almost always progresses to

chronic inflammation following persistent suppuration as a result of uncollapsed abscess
cavities, foreign body materials (dirt, cloth, wool, etc.), sequesterum in osteomylitis, or a
sinus/fistula from chronic abscesses.

4. Autoimmuniy. Autoimmune diseases such as rheumatoid arthritis and systemic lupus

erythematosus are chronic inflammations from the outset.
Morphology:

Cells of chronic inflammation:

 Monocytes and Macrophages are the prima Dona (primary cells) in chronic
inflammation. Macrophages arise from the common precursor cells in the bone
marrow, which give rise to blood monocytes. These cells are then diffusely scattered
in various parts of the body, in the liver (Kupffer cells), spleen, lymph nodes (sinus
histiocytes), lungs (alveolar macrophages), bone marrow, brain (microglia), skin
(Langerhans’s cells). These cells constitute the mononuclear- phagocytic system.
 Macrophages are scavenger cells of the body.

Other cells in chronic inflammation:

1. T-Lymphocytes are primarily involved in cellular immunity with lymphokine

production, and they are the key regulator and effector cells of the immune system.
2. B-lymphocytes and Plasma cells produce antibody directed either against
persistent antigen in the inflammatory site or against altered tissue components.
3. Mast cells and eosinophils appear predominantly in response to parasitic infestations
& allergic reactions.

Though neutrophils are hallmarks of acute inflammatory reactions, large numbers of

neutrophils may be seen in some forms of chronic inflammation, notably chronic
osteomylitis, actinomycosis, & choric lung diseases induced by smoking and other stimuli.

Thus, the overall differentiation points between acute and chronic inflammations include:
Characteristics Acute inflammation Chronic inflammation
Duration Short Relatively long
Pattern Stereotyped Varied
Predominant cell Neutrophils, lymphocytes Macrophages, plasm cells
Tissue destruction Mild to moderate Marked
Fibrosis Absent Present
Inflammatory reaction Exudative Productive

Classification of chronic inflammation:

Chronic inflammation can be classified into the following two types based on histologic
features:

1) Nonspecific chronic inflammation: This involves a diffuse accumulation of

macrophages and lymphocytes at site of injury that is usually productive with new
fibrous tissue formations. E.g. Chronic cholecystitis.
2) Specific inflammation (granulomatous inflammation): Granulomatous inflammation
is characterized by the presence of granuloma. A granuloma is a microscopic aggregate
of epithelioid cells. Epithelioid cell is an activated macrophage, with a modified epithelial
cell-like appearance (hence the name epithelioid). The epitheloid cells can fuse with
each other & form multinucleated giant cells. So, even though, a granuloma is basically
a collection of epithelioid cells, it also usually contains multinucleated giant cell & is
 usually surrounded by a cuff of lymphocytes and occasional plasma cells. There are two
types of giant cells:
a) Foreign body-type giant cells which have irregularly scattered nuclei in presence of
indigestible materials.
b) Langhans giant cells in which the nuclei are arranged peripherally in a horse –shoe
pattern which is seen typically in tuberculosis, sarcoidosis. Giant cells are formed by
fusion of macrophages perhaps by a concerted attempt of two or more cells to
engulf a single particle.

Pathogenesis:

There are two types of granulomas, which differ in their pathogenesis.

A. Foreign body granuloma

These granulomas are initiated by inert foreign bodies such as talc, sutures
(nonabsorbable), fibres, that are large enough to preclude phagocytosis by a single
macrophage and do not incite an immune response.

B. Immune granulomas

Antigen presenting cells (macrophages) engulf a poorly soluble inciting agent. Then, the
macrophage processes and presents part of the antigen (in association with MHC type2
molecules) to CD4+T helper 1 cells which become activated. The activated CD4+ T-cells
produce cytokines (IL-2 and interferon gamma).The IL-2 activates other CD4+T helper cells
and perpetuates the response while IFN-γ is important in transforming macrophages into
epitheloid cells and multinucleated giant cells. The cytokines have been implicated not only
in the formation but also in the maintenance of granuloma. Macrophage inhibitory factor
helps to localize activated macrophages and epitheloid cells.

Causes:

Major causes of granulomatious inflammation include:

a) Bacterial: Tuberculosis, Leprosy, Syphilis, Cat scratch disease, Yersiniosis
b) Fungal: Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis
c) Helminthic: Schistosomiasis
d) Protozoal: Leishmaniasis, Toxoplasmosis
e) Chlamydia: Lymphogranuloma venerum
f) Inorganic material: Berrylliosis
g) Idiopathic: Acidosis, Cohn’s disease, Primary biliary cirrhosis

SYSTEMIC EFFECTS OF INFLAMMATIONS

The systemic effects of inflammation include:

a. Fever
b. Endocrine & metabolic responses
c. Autonomic responses
d. Behavioural responses
e. Leucocytosis
f. Leukopenia
g. Weight loss

a. Fever

Fever is the most important systemic manifestation of inflammation. It is coordinated by the

hypothalamus & by cytokines (IL -1, IL-6, TNF-α) released from macrophages and other
cells.

b. Endocrine and metabolic responses include:

 The liver secrets acute phase proteins such as:

o C-reactive proteins
o Serum Amyloid A
o Complement and coagulation proteins
 Glucocorticoids (increased)
 Vasopressin (decreased)

c. Autonomic responses include:

 Redirection of blood flow from the cutaneous to the deep vascular bed.
 Pulse rate and blood pressure (increased)
 Sweating (decreased)

d. Behavioural responses include:

 Rigor, chills, anorexia, somnolence, and malaise.

e. Leucocytosis is also a common feature of inflammation, especially in bacterial infections.

Its usual count is 15,000 to 20,000 cells/mm3. Most bacterial infections induce neutrophilia.
Some viral infections such as infectious mononucleosis, & mumps cause lymphocytosis.
Parasitic infestations & allergic reactions such as bronchial asthma & hay fever induce
eosinophilia.

f. Leukopenia is also a feature of typhoid fever and some parasitic infections.

g. Weight loss is thought to be due to the action of IL-1 and TNF-α which increase
catabolism in skeletal muscle, adipose tissue and the liver with resultant negative nitrogen
balance.

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