Chapter 2

INFLAMMATION
Sr. No. TOPIC Page No.
1 Acute inflammation 2

2 Vascular events of acute inflammation 2

3 Cellular events of acute inflammation 3

4 Mediators of inflammation 7

Cell-derived mediators 8
Plasma-derived mediators 13

5 Morphological patterns of acute inflammation 14

6 Chronic inflammation 15

7 Granulomatous inflammation 18

8 Important questions 19

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 ACUTE INFLAMMATION

Acute inflammation is a rapid host response that serves to deliver leukocytes and plasma
proteins, such as antibodies, to sites of infection or tissue injury.

Signs of inflammation
Celsus (Roman) named the four cardinal signs of inflammation:
1. Rubor (redness)
2. Tumor (swelling)
3. Calor (heat)
4. Dolor (pain)
Virchow added the fifth cardinal sign ‘funtio laesa (loss of function)’.

Inflammatory cells
In most forms of acute inflammation neutrophils predominate in the inflammatory infiltrate
during the first 6 to 24 hours and are replaced by monocytes in 24 to 48 hours. Macrophages not
only survive longer but also proliferate in the tissues. There are exceptions to this rule: in
Pseudomonas infection, infiltrate is dominated by continuously recruited neutrophils for several
days; in viral infections, lymphocytes arrive first; in some hypersensitivity reactions, eosinophils
may be the main cell type.

Host response
Acute inflammatory response by the host to any agent consists of TWO events:
1. Vascular event
2. Cellular event

VASCULAR EVENTS OF ACUTE INFLAMMATION

In inflammation, blood vessels undergo a series of changes to allow plasma proteins and
circulating cells reach the site of infection or injury. The escape of fluid, proteins, and blood
cells from the vascular system into the interstitial tissue or body cavities is known as exudation.

Vascular reaction begins early in inflammation and consists of:

1. Transient vasoconstriction: Vascular events may begin with transient constriction of
arterioles, lasting a few seconds.
2. Vasodilation: is one of the earliest manifestations of acute inflammation. It is due to the
effect of histamine and nitric oxide (NO) on vascular smooth muscle. Vasodilation results
in increased blood flow, which causes heat and redness (erythema) at the site of
inflammation.
3. Increased permeability: Vasodilation is quickly followed by increased permeability.
Increased permeability is the hallmark of acute inflammation. It is caused by:

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 a. Contraction of endothelial cells: under the effect of histamine, bradykinin,
leukotrienes, neuropeptide substance P. It is ‘immediate transient response’,
which lasts for 15-30 minutes. In some forms of injury, there is a ‘delayed
prolonged response’, which begins after a delay of 2 to 12 hours, and lasts for
several hours or even days. E.g. late-appearing sunburn.
b. Endothelial injury: is caused by direct damage of endothelium in severe injuries
like burns, or by the actions of microbes that target endothelial cells. Neutrophils
that adhere to the endothelium during inflammation may also injure the
endothelial cells.
c. Neovascularization: Newly formed vessels under the influence of vascular
endothelial growth factor (VEGF) are excessively leaky.
4. Stasis: Loss of fluid and increased vessel diameter lead to slower blood flow. As stasis
develops, leukocytes, principally neutrophils, accumulate along the vascular endothelium.
At the same time endothelial cells activated by mediators produced at sites of infection
express increased levels of adhesion molecules. Leukocytes adhere to the endothelium.

The features of hemodynamic changes in inflammation are best demonstrated by ‘Lewis

experiment’. ‘Triple response’ or ‘red line response’ elicited when Lewis struck firmly the inner
aspect of forearm with a blunt point were:
1. red line: occurring within seconds after striking was due to local vasodilation,
2. flare: redness surrounding the red line was due to vasodilation of adjacent arterioles
3. wheal: swelling or edema of surrounding skin was due to transudation of fluid in
extravascular space

CELLULAR EVENTS OF ACUTE INFLAMMATION

The journey of leukocytes from the vessel lumen to the interstitial tissue is called extravasation.
It can be divided into following steps:
1. Margination: In normally flowing blood in venules, blood cells are confined to a central
axial column. Because of blood stasis in early inflammation, white cells assume a peripheral
position along the endothelial surface. This process of leukocyte redistribution is called
margination. Term ‘pavementing’ is used for leucocytes lining the vessel wall.
2. Rolling: Subsequently, leukocytes adhere transiently to the endothelium, detach and bind
again, thus rolling on the vessel wall. Rolling is mediated by ‘selectins’. There are 3 types of
selectins, on leukocytes (L-selectin), on endothelial cells (E-selectin), and on platelets and
endothelium (P-selectin). The ligands for selectins are sialylated oligosaccharides.
Expression of selectins and ligands is regulated by cytokines produced in response to
infection and injury. Tissue macrophages, mast cells and endothelial cells secrete several
cytokines. Histamine, thrombin, and platelet-activating factor (PAF) cause redistribution of
P-selectin from Weibel-Palade bodies to the cell surface of endothelium.

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 These weak rolling interactions slow down the leukocytes and give them the opportunity to
bind more firmly to the endothelium.

3. Adhesion: Inflammatory cells finally come to rest at some point where they adhere firmly
(resembling pebbles over which a stream runs without disturbing them). Cells adhere to the
endothelial cells of post-capillary venules adjacent to the infection. Firm adhesion is
mediated by ‘integrins’ expressed on the surface of inflammatory cells. TNF and IL-1 induce
endothelial expression of ligands for integrins, mainly vascular cell adhesion molecule 1
(VCAM-1, ligand for VLA-4 integrin) and intercellular adhesion molecule-1 (ICAM-1,
ligand for LFA-1 and Mac-1 integrins).

Chemokines activate leucocytes and convert them from low-affinity state to high affinity
state.

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4. Transmigration or diapedesis: is leucocyte migration through endothelium. Transmigration
of leukocytes occurs mainly in post-capillary venules. Chemokines act on the adherent
leukocytes and stimulate them to migrate towards the chemical concentration gradient.
PECAM-1 (platelet endothelial cell adhesion molecule) or CD31 help in the migration of
leukocytes. After traversing the endothelium, leukocytes pierce the basement membrane, by
secreting collagenases. The cells then migrate toward the chemotactic gradient. They adhere
to the extracellular matrix through integrins and CD44.

5. Chemotaxis: After exiting the circulation, leukocytes emigrate in tissues toward the site of
injury by a process called chemotaxis, which is defined as locomotion oriented along a
chemical gradient. Both exogenous (bacterial products) and endogenous substances can act
as chemoattractants. Endogenous chemoattractants include IL-8, C5a and LTB4. These
chemotactic agents bind to specific seven-transmembrane G protein–coupled receptors on the
surface of leukocytes. This increases cytosolic calcium and polymerization of actin.
Polymerized actin accumulates at the leading edge of the cell and myosin filaments at the
back. The leukocyte moves by extending filopodia that pull the back of the cell in the
direction of extension.
6. Phagocytosis: Phagocytosis involves three sequential steps:
a. Recognition and attachment: Phagocytosis is initiated by surface expression of receptors
to recognize microbes like Toll-like receptors (TLRs), G protein–coupled receptors,

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 mannose receptors, scavenger receptors and macrophage integrins [Mac-1
(CD11b/CD18)].

Coating microbes with specific proteins further enhances the process of phagocytosis.
The process of coating a particle, such as microbe, to target it for ingestion
(phagocytosis) is called opsonization, and substances that are coated are called opsonins
(C3b, IgG-Fc, lectins especially mannan-binding lectin). Leukocytes express receptors
for these opsonins- CR1 (for C3b) and FcyRI (for IgG-Fc).
b. Engulfment: After a particle is bound to the surface of phagocyte, cytoplasmic
pseudopods flow around the particle due to activation of actin filaments beneath the cell
wall, engulfing the particle in a phagocytic vacuole. Plasma membrane enclosing the
particle breaks from the cell surface so that phagosome becomes internalized and lies free
in the cell cytoplasm. Phagosome then fuses with one or more lysosomes of the cell and
from phagolysosome.

c. Killing or degradation: Microbes are killed by intracellular and extracellular

mechanisms.
i. Intracellular oxidative killing by ROS: NADPH oxidase present in the cell membrane
of phagosome reduces oxygen to superoxide ion. Superoxide is subsequently
converted into H2O2, which has bactericidal properties.

NADPH oxidase
2O2 + NADPH à 2O2- + NADP+ + H+

Dismutase
2O2- + 2H+ à H2 O2

H2O2 exerts its bactericidal properties through MPO dependent or MPO independent
killing. MPO dependent killing occurs in the presence of halides (chloride, bromide
or iodide) and kill microbes by producing hypochalous acid.

MPO

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 H2O2 + Cl-/Br-/I- à HOCl-/HOBr-/HOI- + H2O
(Chloride, Bromide, Iodide) (Hypochalous acid)

Mature macrophages lack MPO. They carry out bactericidal activity by Haber-Weiss
reaction or Fenton reaction and kill microbes by producing OH- ions (hydroxyl
radical).

ii. Intracellular oxidative killing by lysosomal enzymes: Degranulation of lysosomal

enzymes like protease, trypsinase, phospholipase and alkaline phosphatase kill
microbes.
iii. Non-oxidative intracellular bactericidal killing: Some lysosomal granules do not
kill by oxidative damage. These are hydrolases, lipases, proteases, DNAases and
nitric oxide.
iv. Extracellular mechanisms: Immune mediated lysis of microbes by antigen-
mediated or antibody-mediated mechanisms occur at extracellular level.

MEDIATORS OF INFLAMMATION

Mediators of inflammation have some common properties:

1. Derived from: cells or plasma proteins. Site of synthesis for plasma-protein derived
mediators is liver.

CELL-DERIVED MEDIATORS PLASMA-DERIVED MEDIATORS

1. Vasoactive amines 1. Complement system
2. Arachidonic Acid (AA) metabolites 2. Kinin system
3. Lysosomes 3. Clotting system
4. Platelet Activating Factor (PAF) 4. Fibrinolytic system
5. Cytokines
6. Free radicals

2. Release: they are released from granules or synthesized de novo in response to a

stimulus. Some mediators my stimulate release of other mediators. These secondary
mediators may have similar or opposing action.
3. Targets: they differ in their targets. Their action may differ on different targets.
4. Action: include increased permeability, vasodilation, chemotaxis, fever, pain, tissue
damage. Some of them inhibit or limit inflammation.
5. Life span: They have short life. They are rapidly removed by various mechanisms.

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 CELL-DERIVED MEDIATORS

Vasoactive Amines
Histamine

SOURCE RELEASE ACTION

1. Mast cells 1. Physical injury such as trauma, cold, or 1. Vasodilator
2. Basophils heat 2. Increase vascular
3. Platelets 2. Allergic reactions permeability
3. C3a and C5a These effects are mediated
4. Histamine-releasing proteins derived by binding to H1 receptors
from leukocytes on endothelial cells.
5. Neuropeptides (substance P)
6. IL-1, IL-8 Other effects: itching &
pain

Serotonin [5-hydroxytryptamine (5-HT)]

SOURCE RELEASE ACTION

1. Mast cells 1. Platelet aggregation after contact with 1. Vasodilator
2. Platelets subendothelial collagen, thrombin, ADP, 2. Increase vascular
3. Neuroendocrine and antigen-antibody complexes permeability
cells But it is less potent than
(chromaffin histamine.
cells of GIT,
spleen, CNS)

Neuropeptides (Substance P, neurokinin A, vasoactive intestinal polypeptide (VIP), somatostatin

SOURCE ACTION
1. CNS 1. Increase vascular permeability
2. Peripheral nervous system 2. Pain
3. Mast cell degranulation

Arachidonic Acid (AA) Metabolites (eicosanoids): Prostaglandins (PG),

Leukotrienes (LT), and Lipoxins (LX)
They are the most potent mediators of inflammation.
AA is derived from dietary sources or by conversion from the essential fatty acid linoleic acid. In
cell, it is esterified in membrane phospholipids.

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Release of AA-derivatives:
Mechanical, chemical, and physical stimuli increase intracellular Ca2+

This releases cellular phospholipases (mainly phospholipase A2)

Phospholipase cause release of AA from membrane

AA-derived mediators (called eicosanoids),

are synthesized by cyclooxygenases (COX) & lipoxygenases pathways

Cyclooxygenase pathway eicosanoids:

Activated AA

Cyclooxygenase (COX-1, -2)

PGG2

PGH2 + Free radical

PGD2, PGE2 PGF2α PGI2 TxA2 Resolvins

Produced by mast cells, Endothelium Platelets
macrophages, endothelial cells
Vasodilator Vasodilator Vasodilator Vasoconstrictor Inhibit production of
pro-inflammatory
Increase Increase vascular Increase vascular cytokines
vascular permeability permeability
permeability
Bronchoconstriction Bronchodilator Bronchoconstrictor
Bronchodilator
Chemotactic

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PGD2 is
chemoattractan Inhibits platelet Platelet aggregator
t aggregation

Lipoxygenase pathway eicosanoids:

Activated AA

Lipoxygenase

5-HPETE
(5-hydroperoxy eicosatetraenoic acid)

LTA4

5-HETE LTB4 LTC4, -D4, -E4 Lipoxins (LX)

Chemotactic Chemotactic Vasoconstrictor Inhibitors of inflammation:
inhibit neutrophil chemotaxis and
Increase vascular permeability adhesion to endothelium

Bronchoconstrictor

Lysosomes

Neutrophils and monocytes contain lysosomal granules, which release mediators of

inflammation. Granules either fuse with phagocytic vacuoles containing engulfed material, or the
granule contents are released into the extracellular space.

NEUTROPHILS MONOCYTES &

MACROPHAGES
Primary Secondary Tertiary
(azurophilic) (specific) granules
granules granules (C-particles)
Acid protease Alkaline phosphatase Gelatinase Acid protease
Neutral protease Lactoferrin Acid hydrolases Collagenase
Elastase Gelatinase Elastase
Myeloperoxidase Collagenase Plasminogen activator
Acid hydrolase Lysozyme
Acid phosphatase Vitamin B12-binding
Lysozyme protein
Defensin Plasminogen activator
Phospholipase
Cathepsin G
Action of some of the enzymes: Active in chronic
Acid protease: Degrade bacteria and debris within the phagolysosomes inflammation
Neutral protease: Degrade various extracellular components, such as

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collagen, BM, fibrin, elastin, and cartilage, resulting in the tissue
destruction
Elastase: Degrade virulence factors of bacteria

Platelet Activating Factor (PAF)

PAF is produced by platelets, basophils, mast cells, neutrophils, macrophages, and endothelial
cells.
PAF can elicit most of the vascular and cellular reactions of inflammation.
1. Vascular reactions: It causes platelet aggregation, vasoconstriction and
bronchoconstriction. At extremely low concentrations it induces vasodilation and
increased venular permeability with potency 100 to 10,000 times greater than that of
histamine.
2. Cellular reactions: It causes leukocyte adhesion, chemotaxis, degranulation, and
oxidative burst.

Reactive Oxygen Species (ROS)

Free radicals are chemical species that have a single unpaired electron in their outer orbit. Free
radicals also initiate autocatalytic reactions, whereby molecules with which they react are
themselves converted into free radicals.

Superoxide anion (O2Ÿ ), hydrogen peroxide (H2O2) and hydroxyl radicals (ŸOH) are the major
oxygen free radicals released by leukocytes after exposure to microbes, chemokines and immune
complexes. These free radicals increase the expression of chemokines (e.g., IL-8), cytokines and
endothelial leukocyte adhesion molecules, thus amplifying the inflammatory response.

ROS bring the following effects in inflammation:

1. Endothelial cell damage, with resultant increased vascular permeability
2. Injury to other cell types (parenchymal cells, red blood cells).
3. Inactivation of antiproteases, such as α1-antitrypsin. This leads to unopposed protease
activity, with increased destruction of extracellular matrix.

Nitric Oxide (NO)

Produced by:
L-arginine is converted into NO in the presence of nitric oxide synthase (NOS). There are three
types of NOS. Endothelial and neuronal nitric oxide synthase (eNOS & nNOS) are activated by
increase in cytoplasmic Ca2+. Inducible (iNOS) is induced when macrophages and other cells are
activated by cytokines (e.g., TNF, IFN- γ) or microbial products.

Effect: NO has dual effect

1. Activator of vascular event: vasodilation; half-life of NO is however only seconds
2. Inhibitor of cellular event: reduces platelet aggregation and adhesion, inhibits mast cell–
induced inflammation and leukocyte recruitment

Cytokines

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Cytokines are proteins produced by many cells that play important role in inflammation. TNF-α
and IL-1 are two of the major cytokines that mediate inflammation.

CYTOKINE CELL SOURCE MAIN ACTION

IL-1 Monocyte/macrophage Expression of adhesion molecules
B cells Emigration of neutrophils & macrophages
Fibroblast Role in fever & shock
Endothelial cells Hepatic production of acute phase reactants
Some epithelial cells
IL-6 Same as IL-1 Hepatic production of acute phase reactants
Differentiation and growth of T and B cells
IL-8 Neutrophils Induces migration of neutrophils, macrophages and T-
Monocyte/macrophage cells
T cells Release of histamine from basophils
Fibroblast Stimulates angiogenesis
Endothelial cells
Epithelial cells
IL-12 Neutrophils Formation of T helper cells & killer cells
Monocyte/macrophage
Dendritic cells
IL-17 CD4+T cells Emigration of neutrophils & macrophages
Increases secretion of other cytokines
TNF Monocyte/macrophage Stimulates expression of endothelial adhesion
Mast cells molecules
Basophils Secretion of other cytokines
Eosinophils Systemic effects
B cells
T cells
NK cells
IFN-γ T cells Activation of macrophages
NK cells

Chemokines
Chemokines are small (8 to 10 kD) proteins that act primarily as chemoattractants for leukocytes.
40 chemokines and 20 receptors for chemokines have been identified. They are classified into
four major groups.

CHEMOKINE GROUP EXAMPLE CHEMOATTRACTANT

FOR
α chemokine IL-8 Neutrophils
(C-X-C chemokines)
β chemokine Monocyte chemoattractant protein Monocytes
(C-C chemokines) (MCP-1) Eosinophils
Eotaxin Basophils
Macrophage inflammatory protein-1α Lymphocytes
(MIP-1α)
RANTES

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γ chemokine Lymphotactin Lymphocytes
(C chemokines)
CX3C chemokines Fractalkine Monocytes
T cells

PLASMA-DERIVED MEDIATORS
Complement System

Complement system consists of >20 proteins, some are numbered from C1 to C9. Among the
complement components, C3a and C5a are the most important inflammatory mediators.

Complement pathways:
Complement proteins are present in inactive forms in plasma. They are activated by one of the
three pathways and their functions are as follows:

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Coagulation and Kinin Systems

Inflammation and blood clotting are often intertwined. Inflammation causes vascular endothelial
injury, which exposes Hageman factor (factor XII) to activated platelets, basement membrane
and collagen. This leads to the beginning of intrinsic coagulation pathway, the end product of
which is fibrin.

Activated factor XII (aXII) also activates the kinin system, whose end product is bradykinin and
fibrinolytic system, whose end product is plasmin. Bradykinin increases vascular permeability
and causes pain. Fibrin and plasmin activate the complement system.

MORPHOLOGICAL PATTERNS OF ACUTE INFLAMMATION

Serous inflammation
Characterized by: collection of thin fluid derived from plasma or from the secretions of
mesothelial cells lining body cavities.

E.g.
Skin blister resulting from a burn or viral infection
Ascites, pleural/pericardial effusion

Fibrinous inflammation
Characterized by: fibrin deposition in extracellular space. This happens when there is greater
increase in vascular permeability, leading to passage of large molecules such as fibrinogen.

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E.g. fibrinous exudate in meninges, pericardium and pleura

Microscopically: fibrin appears as an eosinophilic meshwork of threads or amorphous coagulum

Fate:
• Fibrin can be broken down by fibrinolysis and the debris removed by macrophages.
• If not removed, it can stimulate growth of fibroblasts and blood vessels leading to scar
formation. E.g. Fibrous thickening of pericardium and obliteration of pericardial space

Suppurative or purulent inflammation; abscess

Characterized by: production of large amounts of pus or purulent exudate consisting of
neutrophils, liquefactive necrosis, and edema fluid.

E.g.: acute appendicitis, abscess

Microscopically: Abscesses have 3 areas from center to periphery:

1. Central zone of necrotic leukocytes and tissue cells
2. Surrounded by a zone of preserved neutrophils
3. Periphery shows vascular dilation and fibroblastic proliferation indicating chronic
inflammation and repair

Fate: Abscess may be wall off and replaced by connective tissue

Ulcers
Definition: An ulcer is a local defect of the surface of an organ or tissue due to sloughing
(shedding) of inflamed necrotic tissue.

E.g.:
Ulcer in the mucosa of the mouth, GIT and genitourinary tract
Peptic ulcer
Ulceration of skin and subcutaneous tissue of the lower limb due to circulatory disturbances

Microscopically:
Acute stage: there is intense polymorphonuclear infiltration and vascular dilation in the margins
of the ulcer.
Chronic stage: margins and base of ulcer develop fibroblastic proliferation and scarring; and
accumulation of lymphocytes, macrophages, and plasma cells.

CHRONIC INFLAMMATION

Definition

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Chronic inflammation is inflammation of prolonged duration (weeks or months) in which
inflammation, tissue injury, and repair coexist.

It may follow acute inflammation or begin without any acute reaction. E.g. of the latter type are
rheumatoid arthritis, atherosclerosis, tuberculosis, and pulmonary fibrosis.

Causes of chronic inflammation

1. Persistent infection: which are difficult to eradicate, e.g. mycobacteria, certain viruses,
fungi, and parasites evoke delayed-type of hypersensitivity or granulomatous reaction.
2. Immune-mediated inflammatory diseases:
a. Immune reactions against one’s own tissues, leading to autoimmune diseases. E.g.
rheumatoid arthritis and multiple sclerosis
b. Unregulated immune responses against microbes, as in inflammatory bowel
disease
c. Immune responses against allergens, as in bronchial asthma
3. Prolonged exposure to toxic agents:
a. Exogenous: silicosis
b. Endogenous: Atherosclerosis- chronic inflammatory response to endogenous
toxic plasma lipids

Morphologic features
Chronic inflammation is characterized by:
• Infiltration of mononuclear cells- macrophages, lymphocytes and plasma cells
• Tissue destruction
• Attempts at healing by developing fibrosis and proliferation of small blood vessels
(angiogenesis)

Cells of chronic inflammation

Macrophages
They are the dominant cell type of chronic inflammation. The precursor phagocytic cell is
produced in the bone marrow, liberated in blood as monocytes. Monocytes migrate to different
tissues and differentiate into larger cell macrophage. Half-life of monocytes is only 1 day while
that of macrophage is several months to years. The various examples of tissue macrophages are:
• liver (Kupffer cells)
• spleen and lymph nodes (sinus histiocytes)
• lungs (alveolar macrophages)
• CNS (microglia)

Monocytes start migrating early in acute inflammation and within 48 hours they become the
predominant cell type. Upon reaching the tissue they are activated by mediators like:
1. TLR
2. Cytokines (IFN-γ) secreted by T-cells

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Activated macrophages release following products which function differently to serve the
responses of inflammation, injury/repair:
Product Function
Lysosomal enzymes (proteases) toxic to extracellular matrix
Reactive oxygen & nitrogen species toxic to microbes and host cells
Cytokines & chemotactic factors recruit other cells
Growth factors (PDGF, FGF, TGF-β) cause fibroblast proliferation, collagen deposition and
angiogenesis

Fate:
In short-lived inflammation: macrophages disappear by either dying or making their way into the
lymphatics and lymph nodes
In chronic inflammation: they accumulate and locally proliferate

Lymphocytes

Activated macrophages secrete

Cytokines (TNF, IL-1) and chemokines Cytokine IL-12

Recruit lymphocytes Stimulate T-cells

Secrete IFN-γ

Recruit monocytes and activate macrophages

Thus macrophages and lymphocytes have bidirectional effect.

Plasma cells
Develop from activated B lymphocytes and produce antibodies against foreign or self antigens or
altered tissue components.

Eosinophils
Are seen in IgE-mediated immune reactions and parasitic infections. Eosinophils are recruited by
chemokine eotaxin.

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Mast cells
Are widely distributed in connective tissues. They participate in immediate hypersensitivity
reactions, which are stimulated by allergens in food, insect venom or drugs.

Allergens

Bind to IgE antibodies

Fc portion of IgE binds to FcεR1 receptor on mast cells

Activated mast cells release histamine & prostaglandins

GRANULOMATOUS INFLAMMATION

Granuloma
A granuloma is a focus of chronic inflammation consisting of modified macrophages (epithelioid
cells) with scattered giant cells. They are surrounded by a collar of lymphocytes and few plasma
cells. Older granulomas are rimmed by fibroblasts and connective tissue.

Epithelioid cells
have characteristic oval to elongated light staining nucleus (cigar-shaped) with abundant pale
pink granular cytoplasm. Cell borders are indistinct and cell boundaries often merge with one
another.

Giant cells
Frequently epithelioid cells fuse to form giant cells, which may be seen in the periphery or
sometimes in the center of granulomas.
Size of cell: 40 to 50 μm diameter
Nuclei: 20 or more in number
Foreign body–type giant cell: nuclei are arranged haphazardly
Langhans-type giant cell: nuclei are arranged peripherally

Types of granuloma
There are two types of granulomas:
1. Foreign body granulomas: It is caused by foreign material (e.g. talc, sutures, or other
fibers), which is typically present in the center of the granuloma surrounded by
epithelioid cells and giant cells.

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 2. Immune granulomas: are caused by a variety of agents that are capable of inducing a cell-
mediated immune response, e.g. infection by Mycobacterium tuberculosis. The
granuloma of M. TB is called a tubercle, often characterized by the presence of central
caseous necrosis.

Diseases with granulomatous inflammation

Recognition of the granulomatous pattern is important because of the limited number of possible
conditions that cause it.

Disease Cause Tissue reaction

Tuberculosis Mycobacterium Caseating granuloma (tubercle): consists of central
tuberculosis caseous necrosis surrounded by epithelioid cells,
occasional Langhan’s giant cells and rimmed by
fibroblasts, lymphocytes, histiocytes; acid-fast bacilli
present
Leprosy Mycobacterium Tuberculoid leprosy shows noncaseating epithelioid
leprae cell granuloma; acid-fast bacilli are scarce
Syphilis Treponema pallidum Tertiary syphilis shows presence of gumma (tubercle)
in skin, subcutaneous tissue, bone, and joints. The
center of gumma consists of coagulated necrosis and
margins composed of plump, palisading macrophages,
plasma cells and fibroblasts. Treponemes are scant.
Cat-scratch Gram-negative Rounded or stellate granuloma containing central
disease bacillus necrotic area surrounded by histiocytes and epithelioid
cells; the innermost layer shows palisading
arrangement. Few giant cells are seen. The peripheral
zone is made of lymphoid cells
Sarcoidosis Unknown etiology Noncaseating granulomas; only few giant cells
Crohn disease Immune reaction Noncaseating granulomas in the wall of the intestine
against intestinal
bacteria, self-
antigens

IMPORTANT QUESTIONS

SHORT NOTES
1. Cytokines and chemokines in inflammation
2. Phagocytosis
3. Role of free radicals in acute inflammation
4. Role of macrophages in inflammation
5. Granulomatous inflammation
6. Granulation tissue
7. Bactericidal mechanism of Phagocytosis

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SHORT ANSWERS

1. Define cytokines. Give two examples.

Ans. Cytokines are proteins produced by many cells that play important role in inflammation.
TNF-α and IL-1 are two of the major cytokines that mediate inflammation.
2. Enumerate any four types of multinucleate giant cells
Ans. Abnormal: Langhan’s, foreign-body, Reed Sternberg, Touton giant cells
Normal: megakaryocyte, osteoclast, syncytiotrophoblast
3. Name two chemotactic factors for neutrophils
Ans. Endogenous: IL-8, C5a and LTB4
Exogenous: bacterial products
4. Name two chemical mediators of inflammation produced by mast cells.
Ans. Histamine & Prostaglandins
5. Name two acute phase reactants.
Ans. Positive acute phase reactants (increase in plasma concentration in response to
inflammation): C-reactive protein, serum Amyloid A, Haptoglobulin, ceruloplasmin, 2-
Macroglobulin, Fibrinogen, Complement C3, C4
Negative acute phase reactants (decrease in plasma concentration in response to
inflammation): albumin, transferrin, transthyretin, retinol-binding protein
6. Intra phagocytic microbial mechanisms.
Ans. Intracellular mechanisms:
1. Oxidative killing by reactive oxygen species (ROS)
2. Oxidative killing by lysosomal enzymes protease, trypsinase, phospholipase and
alkaline phosphatase
3. Non-oxidative killing by lysosomal enzymes hydrolases, lipases, proteases, DNAases
and nitric oxide
Extracellular mechanisms: immune mediated
7. C-reactive proteins
Ans. Is a substance produced by liver, which increases in plasma concentration in response to
inflammation. It is a non-specific marker for disease.

The End

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