Inflammationand Repair

DEFINITIONS AND GENERAL FEATURES (p 70)

DEFINITION AND CAUSES

Inflammation is defined as the local response of living mammalian tissues

i u y from any agent. It is a body defense reaction in order to eliminate
r limit the spread of injurious agent, followed by removal of the necrosed
cells and tissues.

The injurious agents causing inflammation may be as under: (1) Infective

bacteria, viruses and their toxins, fungi, parasites; (2) Tissue
agentslike
necrosis caused by various agents such as ischaemia, physical agents (e.g.
heat. Cold, radiation, mechanical trauma), or chemical agents (e.g. organic
and inorganic toxins); (3) immunological agents like cell-mediated and antigen-
etc.
antibody reactions; (4) inert matenas such as foreign bodies, dirt, sutures
SIGNS OF INFLAMMATION

Although the word inflammation means burning, we now know that buming
of inflammation. Roman medical writer Celsus in
isonly one of the features
1st century A.D. described famous 4 cardinal signs of infammation as: ()
rubor (redness); (i) tumor (swelling); (ii) calor (heat); and (iv) dolor (pain).
To these, fifth sign functio laesa (loss of function) was later added by
Galen, a pupil of Hippocrates.

TYPES OF INFLAMMATION

Depending upon the defense capacity of the host and duration of response,
inflammation can be classified as acute and chronic:
Acute inflammation is ofshort duration (lasting less than 2 weeks) and
the early body reaction, resolves quickly and is usually followed
represents
by healing.
I. Chronic inflammation is of longer, duration and occurs after a delay,
either when the causative agent of acute inflammation persists for a long time,
or the stimulus i such that it induces chronic inflammation from the beginning.

INITIATION OF INFLAMMATION (RECOGNITION OF ETIOLoGIC

AGENTS)
Inflammation is initiated due to presence of a recognition system of receptors
Detween the etiologic agent (i.e. microbes, necrotic cells) and the participating
host cells; besides, a few circulating proteins too act to trigger inflammation:
1. Recognition system of receptors There are distinct receptors on host
cells for microbial agents, leucocytes and for necrotic cells.

2. Circulating proteins Another set of initiators of inflammation are certain

after
irculating proteins liberated by activation of complement system
crobial infection. These include mannose-binding lectins and collectins.

ACUTE INFLAMMATORY RESPONSE (p71)

RCule inflammatory response by the host to any etiologic agent is a continuous
process but for the purpose of discussion, it can be divided into following two
components: (i) Vascular events; and (i) Cellular events.

(43)
 VASCULAR EVENTS (p 71)
Alteration in the microvasculature (arterioles, capillaries
laries and
and veni
earliest response to tissue injury. venules) is he
HAEMODYNAMIC CHANGES

The earliest features of inflammatory response result from chana

vascular flow and calibre of small blood vessels in the injured tin the
sequence of these changes is as under: (1) Transient vasoconstrihe
arterioles; (2) Persistent progressive vasodilatation; (3) Elevate n of
hydrostatic pressure; (4) Slowing or stasis of microcirculation0al
Leucocytic margination. 5)
TRIPLE RESPONSE The features of haemodynamic changes in inflamma
are best demonstrated by the Lewis experiment. In this experiment o n
eriment, the skin
of inner aspect of foream is stroked firmly with a blunt point and
observed. The reaction so elicited is known as tniple response or r changes
red
response oconsisting of the following: (0) Red line appears within a few s
after stroking; this is due to local vasodilatation of capillaries and venules
Flare is the bright reddish appearance or flush surrounding the red ine:t
results from vasodilatation of the adjacent artenoles, and (ii) Wheal is tho
sweling or oedema of the surrounding skin; this ocCurs due to transudatian
of fluid into the extravascular space.
These features, thus, elicit the classical signs of inflammation-redness
heat and swelling, to which fourth feature, pain due to mild trauma to
cutaneous nerve endings, has been added.

ALTERED VASCULAR PERMEABILITY

In and around the inflamed tissue, there is accumulation of oedema fluid in the
interstitial compartment which comes from blood plasma by its escape through
the endothelial wall of peripheral vascular bed. In the initial stage, escape of fluid
is due to vasodilatation and consequent increased volume of blood, elevating
hydrostatic pressure. This is transudate in nature. But subsequently, the
characteristic infammatory oedema, exudate, appears by increased vascular
pemeability of microcirculation and by appearance of inflammatory cells.

MECHANISMS OF VASCULAR LEAKINESS

Increased vascular pemeability in acute inflammation by which normally non-
pemeable endothelial layer of microvasculature becomes leaky by following
mechanisms which may be acting singly or in combination: () Contraction of
endothelial cells; (i) Contraction or mild endothelial damage; (i) Direct injury
to endothelial cells; (v) Leucocyte-mediated endothelial injury, () Transcytosis
across the endothelial cytoplasm; and (vi) Leakiness in neovascularisation.

CELLULAR EVENTS (p 73)

The cellular phase of acute inflammation includes recruitment of leucocytes at
the site of infection, their activation to recognise the microbe, and eventuaily
phagocytose and clear off the offending agent.

EXUDATION OF LEUCOCYTES
Escape of leucocytes from the lumen of microvasculature to the interstl
tissue is the most important feature of inflammatory response. In acu
infammation, polymorphonuclear neutrophils (PMNs) comprise the irs
of body defense, followed later by phagocytes (monocytes and macropnage
The changes leading to migration of leucocytes are as follows:
1. CHANGES IN THE FLOW OF BLOOD In the early stage of inflammau
the rate of flow of blood is increased due to vasodilatation. But subseq
there is slowing or stasis of bloodstream. Due to slowing and stasis, une s
siream of cels widens and peripheral plasma zone becomes naTowero AsS
of loss of plasma by exudation. This phenomenon is known as marginau t
a resutt of this redistribution, neutrophils of the central column come
the vessel wall; this is known as
pavementing.
 45
ING AND ADHESION Peripherally marginated and pavemented
ROLLIN

h i s slowly roll over the endothelial cells lining the vessel wall (rolling
This is followed by transient sticking ofleucocytes to endothelial cells
phasnohase). The process of rolling is facilitated by following cell adhesion
molecules (CAMs or adhesion receptors (ARs). CAMs are expressed in
ines (TNF, IL-1, chemokines) produced after exposure to
response to cytokine.

P-selectin, E-selectin, and

rnhial infection and cell damage: (i) Selectins:
L-selectin: (i) Integgrins: B-1 integrin and B-2 integrins.
neutrophils
TRANSMIGRATION After leucocyte-endothelium adhesion, the endothelial
between
endothelal surtacetilla suitable site
move along thewhere the neutrophils throw out cytoplasmic pseudopods.
olls is found of red cells through
Simultaneous to emigration
of leucocytes, escape
endothelial cells takes place.
aa0s between the
Chemotaxis is movement of leucocytes towards
CHEMOTAXIS
molecules or factors called chemoattractants.
the direction of chemical
after crossing several bariers (endothelium,
Transmigration of leucocytes to reach the
membrane, perivascular myofibroblasts and matrix)
basement
chemotactic factor-mediated process. Chemoattractants
interstitial tissues is a
be of two types:
for leucocytes may Most important exogenous substances are
soluble
(1) Exogenous agents as
formylated peptide.
bacterial products such These include several chemical mediators e.g. (i)
(2) Endogenous agentsa of lipoxygenase pathway of arachidonic acid
Leukotriene B4 (LT-B4), product
system (C5a in particular); (ii)
metabolites; (i) Components complement
of
eotaxin etc); (iv) Kallikerin,
Cytokines/chemokines (e.g. IL-8, MCP-1, MIP-a,
end-product of the kinin system.

PHAGOCYTOSIS
by
infiltrated leucocytes, process of clearing
After the site of infection has been in action. Phagocytosis is defined as the
the microbial agent is set
off of of a solid particulate material (e.g. microbes,
process of cellular engutfment
in other words phagocytosis is cell-eating (on
foreign particulate material); called pinocytosis). The cells performing
this
is
the other hand, cell-drinking
function are called phagocytes. involves
Phagocytosis of the microbe by polymorphs and macrophages
the following 3 steps

1. RECOGNITION AND ATTACHMENT

of cell surface receptors on
Phagocytosis is initiated by the expression mannose receptor and
macrophages which recognise microorganisms:is further enhanced when
Scavenger receptor. The process of phagocytosis opsonins, from the
proteins,
the microorganisms are coated with specific(meaning preparing for eating)
serum and the process is called opsonisation
and (ii) Collectins.
e.9-0lgG opsonin; (i) C3b opsonin;
2. ENGULFMENT
to the surface of phagocyte is ready
he opsonised particle or microbe boundformation of cytoplasmic pseudopods
O be engufed. This is accomplished by
actin filaments beneath cell wall,
around the particle due to activation of
enveloping it in a phagocytic vacuole.
3. KILLING AND DEGRADATION
cells is klling degradation
and
he major function of phagocytes as scavenger
of microbe to dispose it off. The microorganisms after being killed by
anibacterial substances are degraded by hydrolytic enzymes.
in general, following mechanisms are involved in disposal of microbes:
A Intracellular mechanisms: () Reactive oxygen species e.g. (a) MPO-
Oependent and (b) MPO-independent; (i) Nitric oxide; and (ii) Lysosomal
granules.
 Neuopnil
46 Activated leucocytes;
(i)
8 Extracellular mechanisms: (i)
Immune mechanisms
extracellular traps (NE Ts), and (ii)

CHEMICAL MEDIATORS OF
INFLAMMATION (p 77
endogenous
chemical substances
number of
These are a large and increasing
of acute and chronic
inflammation
which mediate the process chemical mediators of
substances acting as
Two main groups of from the plasma proteins, and
i n f l a m m a t i o n - r e l e a s e d from the
cells and those
and discussed below. Thei
listed in Table 4.1 are
members in each group are illustrated in Fig. 4.1,
inflammation is schematically
range of actions in acuste

Table 4.1 Mediators of inflammation.

L CELL-DERIVED MEDIATORS

1. Vasoactive amines
(Histamine, 5-hydroxytryptamine, neuropeptides)
acid metabolites (Eicosanoids)
2. Arachidonic
Metabolites via cyclo-oxygenase pathway
(prostaglandins,
thromboxane A prostacyclin, resolvins)
Metabolites via lipo-oxygenase pathway
(5-HETE, leukotrienes,
i
lipoxins)
3. Cytokines: interleukins (L-1, IL-6, IL-8, IL-12, IL-17) TNF-a,TNF-B;
IFNT other chemokines)
4. Platelet activating factor
nitric oxide)
5. Free radicals (Oxygen intermediates,
LPLASMA PROTEIN-DERIVED MEDIATORS (PLASMA PROTEASES

Products of
1. The kinin system (kallikrein, bradykinin)
2. The dotting system (fibrin, fibrinopeptides)
3. The fibrinolytic system (plasmin)
4. The complement system (3a, 3b, C5a, MAC)

INFLAMMATORY CELLS (p 84)

The cells participating in acute and chronic infammation are circulating
cells
leucocytes, plasma cells, tissue macrophages and infammatory giant 42
characteristics and functions are summarised in Table
Their morphology,

GIANT CELLS
Giant cells are fomed by fusion of various cells. They have following genea
features: (a) Large size (40-120 um in diameter); (b) Contain multiple nude
(often 15-30) or more, and (c) Their phenotype depends, upon the charade
of cell from which giant cell is derived.
Multinucleate giant cells may be normally seen in certain tissues 89
osteoclasts in the bones, syncytiotrophoblasts in placenta, megakary00ys
in the bone marow. Pathokogic giant cells may be seen in someinfammau
conditions, or they may occur as tumour giant cells in certain neoplasis.
MACROPHAGE-DERIVED GIANT CELLS These giant cells are formed o
fusion of macrophages in chronic infammation when macrophages fail lo 06
with microbe or particulate material for its removal. These are of three YP
Langhans', foreign body, and Touton type.
from
EPIDERMAL CELL-DERIVED GIANT CELLS Giant cells formeddema
epidermal cells may be Tzanck giant cells, or rarely multinucleate epu
giant cells.

FACTORS DETERMININGVARIATION IN RESPONSE (p87)

The variation in infammatory response depends upon a numoe
and processses. These
may pertain to the organisms and the nos
 MEDIATOOR MAIN ACTION
sOURCE
1 Permeability

Mast cells, basophils, platelets Histamine

CELL Platelets Serotonin Permeability

DERIVED
Prostaglandins Vasodilatation
Leucocytes
Leukotrienes Permeability
Lysosomalenzymes Tissue damage
Platelet-activating factor
Permeability
Cytokines
Fever

Nitric oxide and oxygen Tissue damage

Metabolites

Clotting and fibrinolytic system Fibrin split products Permeability

PLASMA Kininsystem
PROTEIN Kinin/bradykinin T Permeability
DERIVED
Complement system Anaphylatoxins T Permeability
C CaCsa C
Figure 4.1 Mediators of inflammation.

eday pue uonewuejuj 83LdVHD

48 Table 4.2 Morphology and functions of inflammatory celle
MAIN FUNCTIONS FEATURES
A, POLYMORPH

) Initial phagocytosis of bacteria ) Primary granules (MPO,

and foreign body cationic proteins, acid lysozyme
i) Engulfment of antigen-antibody elastase) hydrolaser
complexes ) Secondary granules (lysozyme
i) Basement membrane alk. phosph, collagenase,
destruction lactoferrin)
iv) Acute inflammatory cell ii) Tertiary granules
cathepsin) (gelatinase,
B, EOSINOPHIL
i) Allergic states ) Contains MPO
i) Parasitic infestations ) Granules contain major
ii) Dermatoses protein, cationic proteinbasic
iv) Malignant lymphomas ii) Lack lysosomes
v) Chronic inflammatory cel
C BASOPHIUMAST CELL
)Receptorfor lgE molecules Histamine
i Electron-dense granules ii) Leukotrienes
ii) Platelet activating factor
D, LYMPHOCYTE
i) Humoral and cell-mediated i) Bcells: antibody
immune responses i) Tcells: delayed production
i) Chronic inflammatory cell hypersensitivity
ii) Regulates macrophage cytotoxicity
response
E,PLASMACELL
i) Derived from Bcells i) Antibody synthesis
i) Plasma cell dyscrasias
ii) Antibody secretion
ii) Chronic inflammatory cell
F, MONOCYTE/MACROPHAGE
Microbial phagocytosis and
i)Require activation by: classic
killing (non-immunologic) or alternate
i) Induce repair by fibrosis
ii) Chronic (IL-4, IL-13) way
iv) Regulate
inflammatory cell i) Release proteases (collagenase
lymphocyte response elastase)
ii) Activation of coagulation
pathway
iv) Prostaglandins, leukotrienes
Chemoattractant for other
leucocytes
FACTORS INVOLVING THE
ORGANISMS
0
Types of injury and infection; (i) Virulence; (ii) Dose; Portal ot
and (v) Product of (iv) enu
organisms.
FACTORS INVOLVING THE
HOST
0 Systemic diseases; (i) Immune
defects; (v) status of host; (ii)
Congenital
host factors. Leukopenia; (v) Site or type of tissue involvea, OCal
a
MORPHOLOGIC PATTERNS OF ACUTE
Innammation of an organ ls INFLAMMATION (p 88
name e.g. usually named by adding the suffix -is s Latin

1.
appendicitis, hepatitls,
cholecystitis, meningitis ec.
CLASSIFICATION
1eBIon ls OF
INFLAMMATROY REACTION An Inflammatory

affected:
cassified based on RE
duration, type of exudates a t o m i c
l o c a t i o n

and
aine
CHAPTER 4Inflammationand Repair
!H
Kbojoyed jeiauag INOIL3s
CHAPTER4Inflammation and Repair
as HO
LLI
2 MORPHOLOGY OF GRANULOMA In general, a granuloma
oma ha has the
stnuctural composition:
called because of their anie
folowing
cells These are so

s/histiocytes whichaithelial cel-

1. Epithelioid
appearance. They are modified macrophages/h are
elongated cells having
slipper-shaped nucleus.
somewhat
2. Multinucleate giant cells Multinucleate giant cells areformed
of adjacent epithelioid cells and may have 20 or more nuclei. by f
may be arranged at the peripherylike the orseshoe or as a ring nese nuclei
clustered at the two poles (Langhans giant cells), or they mav may ba
giant cells).
may be present
centrally (foreign body
3. As a
Lymphoid cells cel-mediated immune reaction to
response by lymphocytes (predominantly
T cells) is integral ntigen,
to
the host
of a granuloma. composition
4 Necrosis Necrosis may be a feature of some granulomatous.
e.g. central caseation necrosis in erculosis, so called because of onditions
cheese-like appearance. dry
5 . Fibrosis Fibrosis is a feature of healing by proliferating fibroblasts at ts.
periphery of granuloma.

COMMON EXAMPLES OF GRANULOMATOUS INFLAMMATION p 93)

Granulomatous inflammation is typical of reaction to poorly digestible
These agents may be infectious or non-infectious: agente

A. Infectious causes These are mycobacteria (e.g. tuberculosis, lepros

bacteria (e.g.
actinomycosis), spirochetes (e.g. syphilis), fungi infections (e.g.
cryptococcosis), parasites (e.g. schistosomiasis).
B. Noninfectious causes These include exogenous agents
particles, berylliosis etc), and immune causes (e.g. Crohn's (e.g. foreign
disease).
TUBERCULOSIS (p 93)
Tissue response to causative
agent, Mycobacterium tuberculosis, represents
classical example of chronic
granulomatous inflammation in humans.
INCIDENCE
Factors contributing to
higher incidence of tuberculosis are malnutrition,
inadequate medical care, poverty, crowding, chronic
such as uncontrolled debilitating conditions
diabetes, alcoholism and immunocompromised
In the western
to HIV-AIDs.
countries, there has been a resurgence of tuberculosisstales.
due

ETIOLOGIC AGENT
Tubercle bacillus
(TB) or Koch's bacillus
causes Mycobacterium tubercuios
tuberculosis in the lungs and other tissues
or

organism is a strict aerobe and of the human body.

tension such as in the thrives best in tissues with high oAY
apex of the
lung.
M.tuberculosis hominis is a slender
rod-like bacillus, 0.5 um by
neutral on Gram staining, and can be demonstrated
(1) Acid fast (Ziehl-Neelsen) staining; (2) by the following t
methods; (4) Molecular methods; (5) Fluorescent method, (9)
and (6)
Serologic tests. Immunohistochemical staln, a

ATYPICAL MYCOBACTERIA
The term
atypical
(NON-TUBERCULOUSMYCOBACTERIA) (NTM) Is
u8ed for mycobacteria or non-tuberculou
rculous mycobacteria andM
mycobacterial species other than M. tuberculosis complex
leprae. NTM are widely also
called as distributed in environm
environmental mycobacteria.theThe nment and are, therefd
They too are acid fast. NTM
are
non

patnogenic to guinea pigs but occasionally may cause huia t

u b e r c u l o s i s

whlch ls resistant
to usual
anti-tubercular drugs.
jeday pue uonewuegujt8LdVHD
Table 4.3 Differences between primary and secondary tubercusir
FEATURE PRIMARY TUBERCULOSISs SECC TUEEKU
Children and aduts,
1. Age and Mostly children who are
not previously sensitised to ether due to reactiv
evolution
tubercle bacilli of primary forus or by
reinfection

2. Organs Almost exclusive in lungs Lungs, lymph nodes, rhe

organs gentourinary tars
bones, meninges, brain,
eye, liver, spleen, intesre
skin etc).

Lower part of upper lobe Apex of lungs where

3. Distribution
and upper part of lower oxygen tension is high
lobe

4. Lesions Ghon's complex (lung Simon's focus Qung lesion

lesion as consolidation
lymphatic vessel and hilar
lymph nodes lesions)
5. Severity Generally asyptomatic, less
severe
as tuberdes, extensive
caseation, miliary
lesions, cavítary lesions,
fibrocaseous lesions,
caseous pneumonia,
pleurisy/effusion)
Usually symptomatic, more
severe

6. Fate Healing by fibrosis, Consolidation, parendiya

calcification, may get nodules, thidkened pleu
reactivated in weakened amyloidosis, reactivationd
immunity healed lesion in impaired
immunity and AIDS

A. PRIMARY TUBERCULOSIS
Infection of an individual who has not been previously infected or immurisad
is called primary tuberculosis or Ghon's complex or childhood tuberaulosis
lesion produced in the fisLed
Primary complex or Ghon's complex is the
vessels and lymph nodes les
portal of entry with foci in the draining lymphatic
commonly involved tissues for primary complex are lungs and hilar lymph nodes
The incidence of disseminated fom of progressive primary tubercioss
is paricularly high in immunocompromised host e.g. in patients ofÍ AIDS
Primary complex or Ghon's complex in lungs consists of 3 componenis
vessel component, and (3)L
(1) Pulmonary component; (2) Lymphatic
node component.
FATE OF PRIMARY TUBERCULOSIS Primary complex may have C
the following consequences: (1) Heal by fibrosis; (2) Progressve prn
Healed lesi
tuberculosis; (3) Primary miliary tuberculosis; and (4)
activated and cause progressive secondary tuberculosis.

B. SECONDARY TUBERCULOSIS ensisad

Infection of an individual who has been previously infected o

or chronic thubert
is called secondary, or post-primary or reinfection, dogenos

The routes of infection in secondary tuberculosis may

sOUrce such as reactivation of domant primary complex; or exog
Such as fresh dose of reinfection by the tubercle bacil Othersilesa
Secondary tuberculosis occurs most cormmonly in lungs.e n
aym
USSues which can be involved are lymph nodes, tonsis, phiay
intestine and skin.

SECONDARY PULMONARY TUBERCULOSIS beginas1 2 0

The lesions in secondary pulmonary berculosis usually

e n t i yd e v e l o p s

apical area of consolidation of the lung which subse

 55
caseation necrosis and later may develop peripheral fibrosis. It may occur
by lymphohaematogenous spread of infection from reactivation of primary
complex to the apex of the affected lung where the oxygen tension is high

andfavourable for growth of aerobic tubercle bacilli, or the infection may be

direct reinfecti
the result of

PULMONARY TUBERCULOSIS
FATE OF SECONDARY
lesions in lungs can develop following outcomes:
Subapical tuberculous
heal with fibrous scarring and calcification; (2) The
(1) The lesions may
lesions may coalesce together to form larger area of tuberculous pneumonia
tuberculosis with the
and produce progressive secondary pulmonary
following pulmonary and extrapulmonary involvements e.g. (i) Fibrocaseous
tuberculosis: (i) Tuberculous caseous pneumonia; (ii) Miliary tuberculosis;
(iv) Tuberculous empyema.
4.3 depicts various
Fig. pulmonary and pleural lesions in tuberculosis.

Miliary tubercles Cavitary tuberculosis

Tuberculosis of
hilar lymph Tuberculous
nodes pleurisy
Caseous
pneumonia

Tuberculous
Ghon's empyema
focus

and pleura in various types of

Figure 4.3 Spectrum of lesions in the lungs
pulmonary tuberculosis.

CLINICAL FEATURES AND DIAGNOSIS

1. Referable to lungs-such as productive cough (may be with haemoptysis),
show typical
effusion, dyspnoea, orthopnoea etc. Chest X-ray may
pleural diffuse infiltrates
apical changes like pleural effusion, nodularity, and miliary
or

in the lung parenchyma.

2. Systemic features-such as fever, night sweats, fatigue, loss of weight
and appete. Long-standing and untreated cases of tuberculosis may develop
systemic secondary amyloidosis.
be made by following
Diagnosis of tuberculosis in a suspected case can
tests: (i) AFB microscopy of diagnostic specimen such as sputum, aspirated
method on LJ medium for
material; (i) Mycobacterial culture (traditional
4-8 weeks, newer rapid method by HPLC of mycolic
acid with result in 2-3
haemogram
weeks); (ii) Molecular methods such as PCR; (iv) Complete
and raised ESR); (v) Radiographic procedures e.g. chest
(lymphocytosis
and other parenchymal changes);
X-ray showing characteristic hilar nodules release
Interferon gamma
(i) Tuberculin skin test (TST, Mantouxtest): (vii) of cytokine
elispot) is
measure
a
assay (1GRA) (e.g. quantiferon-TB-gold,
advocated as a substitute to tuberculin
skin test.
released in blood and is
antibodies are not useful
However, serologic tests based on detection of
some developing countries
but are not
although these are being used in
56 recommended by the WHO for diagnosis of tuberculos
needleaspiration cytology of an enlarged peripheral vmanph and vi) Fina
useful and easy way for confirmation of diagnosis and hae
and has node is
the biopsy diagnosis of tuberculosis. largely qite
Causes of death in pulmonary tuberculosis are is replacAd
insufficiency, pulmonary haemorrhage, sepsis due to Sualy
disser
puimonary
tuberculosis, cor pulmonale or secondary amyloidosis
aminaled miliany
LEPROSY (p 103)
Leprosy or Hansen's disease, is a chronic non-fatal infectin
affects mainly the cooler parts of the body such as the skin m s diseao.
tract, eyes, peripheral nerves, superticial lymph nodes and testi
the earliest and main involvement is of the skin and nerves testis.respi
In lerprosy
a
CAUSATIVE ORGANISM
The disease is caused by Mycobacterium lepraee which
which
closely.
Mycobacterium tuberculosis but the organism is less acid. cosely
characteristic neurotropism. The organisms in
tissues appear aeha
fastresembles
rounded masses (globi) or are arranged in parallel fashion
like ciaarotmpact
M. leprae can be demonstrated in tissue
sections, in split skin ePack,
splitting the skin, scrapings from Cut edges of dermis, and in nears by
by the following techniques: (1) Acid-fast (Ziehl-Neelsen nasalssm
or ZNI s
(2) Fite-Faraco staining: (3) Gomori methenamine silver
(4) Molecular methods e.g. PCR. (GMS) staininos
and
INCIDENCE
The disease is endemic in areas with hot and
moist
tropical countries. Leprosy is almost exclusively a diseaseclimates
of a
and in noa
0o
countries in Asia, Africa and Latin America. few develoninn
ing
MODE OF TRANSMISSION
Leprosy is a slow communicable disease and the incubation
first exposure and period between
appearance of signs of disease varies from 2 to 20
(average about 3 years). The infection may be transmitted the years
routes: (1) Direct contact with untreated by following
leprosy patients,
transmission across the placenta, and (3) Transmission (2) Matemo-foetal
from milk of leprosy
affected mother to infant.

IMMUNOLOGY OF LEPROSY
Like in tuberculosis, the immune
response in leprosy is also T cell-mediated
delayed hypersensitivity (type IV reaction) but the two diseases are quite
dissimilar as regards immune reactions and
lesions. M. leprae do not produce
any toxins but instead the damage to tissues is immune-mediated.
LEPROMIN TEST It is not a
on the basis of immune
diagnostic test but is used for classifying leprosy
response. Intrademal injection of lepromin, an
extract of M. leprae, reveals anige
delayed hypersensitivity reaction in patienis
tuberculoid leprosy.
The test indicates that cell-mediated immunity is greatly suppress in
lepromatous leprosy while patients of mune
response. tuberculoid leprosy show gooo
CLASSIFICATION
RIDLEY AND JOPLING'S CLASSIFICATION Traditionally, fomsof
eprosy two
are distinguished: (1) Lepromatous type representing maefalnc
and (2)
Tuberculoid type representing owi
high resistance.
Salient diferences between these two foms of leprosy ae a r e s u m m a r i s e d

in Table 4.4.
eday pue uogewueyuj 31dVH
58
leprosy like LL and BL offers no problem while the indetermin
tuberculoid lesions are paucibacillary and their
with clinical evidence
diagnosis is diagnosis eprony
made to
and
In general, for histopathologic evaluation of skin
ogether
cases of leprosy, the following general features biopsy in
bea
o

(i) Cell type of granuloma; (i) Nerve

should
involvement; sUspocl
looked efodr
(iv) Presence and absence of lymphocy
with epidermis and adenexa.
and () Relation ofcterial load
ii)
granuloma
CLINICAL FEATURES

1 . LEPROMATOUs LEPROSY
(i) The skin lesions in LL are
generally symmetrical,
hypopigmented and
erythematous macules, papules, multipla
may coalesce to nodulae1ghtly
infiltrates. The nodular lesion
appearance, and (i) The lesions are give leonine diffuse
hypoaesthe or facies
sensory disturbance is not as distinct as in TT. anaesthetic bubut the
2. TUBERCULOID LEPRoSY

0) The skin lesions in TT occur as

lesions which are either single or as a
few
is a distinct hypopigmented
sensory impairment.
and
erythematous macules; asymmetrical
and (i) Thera
Long term cases of either
type may develop
secondary amyloidosis.
SYPHILIS (p 107)
Syphilis is a venereal
Treponema pallidum, (sexually-transmitted) disease caused by
by periods of latency. characterised by episodes of active diseasespirochetes,
interrupted
CAUSATIVE ORGANISM
T. pallidum is a
coiled spiral filament 10
preparations. The organism cannot be stained
be
um long that moves
actively in fresh
demonstrated in the exudates and by the usual methods and can
(DGI) in fresh tissues by: (1) dark
preparation; (2) fluorescent antibody ground illumination
impregnation techniques, and (4) nucleic acid technique; (3) silver
amplification technique by PCR.
IMMUNOLOGY AND TESTS
T.
pallidum does not
of the lesions produce any endotoxin or exotoxin.
The
immune response. pathogenesis
appears to be due to host
Besides direct
two types of demonstration of the organism
serological tests for discussed above, there di
A.
Treponemal syphilis: treponemal and
absorbed (FTA-ABS) serological tests: (i) Fluorescent non-treponena
assay for T. pallidumtest; (ii) Agglutinin assays e.g. treponemal anub
ination
sensitive, and (ii) T. (MHA-TP), and Serodia TP-PA; microhaemaggiuuo
the more
pallidum passive later
B. haemagglutination (TPHAJ 1
Non-treponemal serological tests:
fixation (RPCF) test. (i) Reiter
Disease Research Test of choice for rapid diagnosis, protein com a ement

Laboratory
Wassermann described a (VDRL) or Rapid Plasma
and
01 test
human syphilitic tissue. Thiscomplement fixing keagntiaen
ng antibody against antige of
(STS) Wassermann
in antigen used in the
is r Syphilis
complement fixing test and Standard
VDRL test
lest
MODE OF TRANSMISSION
(1) Sexual transmission
route of infection and (heterosexual or nomosexual) is
and rectum; results in lesions onhomosexual) is the tnei
most commo
vagina, cerviX
(2) Intimate glans penis, vulva, va
tongue or fingers; (3) person-to-person
Transfusion of infected
contact with le
lips,
Hoetal

transmission in congenital
syphilis if the motherblood;
and (4) Mai
is infected.
D

eday pue uoueuueyuj t 83LdVH

 SECTION 1General Pathology

9
 (D

eday pue uopeuueyuj 83LdVHD

62
SELECTED EXAMPLESOF TISSUE REPAIR (p 116)
HEALING OF SKIN WOUNDS (p 116)
Wound healing can be accomplished in one of the followin
() Healing by first intention (primary union); (i) Healing by ing two ways
(secondary union). second intention
HEALING BY FIRST INTENTION (PRIMARY UNION)
This is defined as healing of a wound which has the followina chor
) clean and uninfected; (i) surgically incised; (ii) without much lscs
and tissue; and (iv) edges of wound are approximated f cells
by suraical o
The sequence of events in primary union is: (1) Initial
haemorrha sutures
Acute inflammatory response; (3) Epithelial changes;
(4) Organisati2
(5) Suture tracks. , and
The scar formed in a sutured wound is neat due to
close appositionof
margins of wound; the use of adhesive tapes or metal clips avoids of the
of stitches and its complications. remu
moval
HEALING BY SECOND INTENTION (SECONDARY
UNION)
This is defined as healing of a wound
having the following characteristics:.
open witha large tissue defect, at times infected;
cells and tissues; and (ii) the wound is not
(i) having extensive loss of
but is left open. approximated by surgical sutures
The
basic events in secondary union are similar to primary union but
in having a larger tissue defect which difer
has to be bridged.
The sequence of events in
secondary union is: (1) Initial haemorrhage: (2)
Inflammatory phase; (3) Epithelial changes; (4) Granulation tissue; (5) Wound
contraction; and (6) Presence of infection.
Differences between primary and
in Table 4.5. secondary union of wounds are given

Table 4.5
Differences between primary and secondary union of
wounds.
FEATURE PRIMARY UNION SECONDARY UNION
1. Cleanliness of Clean
wound Unclean

2. Infection
Generally uninfected May be infected
3. Margins h Surgical clean Irregular
4. Sutures
Used Not used
5. Healing Scanty granulation tissue Exuberant granulation
at the incised gap and tissue to fill the gap
along suture tracks
6. Outcome
Neat linear scar Contracted irregular
wound
7. Complications
Infrequent, epidermal Suppuration, may requilre
inclusion cyst formation debridement

COMPLICATIONS IN HEALING OF SKIN WOUNDs

(1) Infection; (2) ( 4 )D e f i c i e n t

Implantation (epidermal) cyst; (3)

Scar formation; (5) Incisional hernia; (6)
formation, and (7) Excessive
Pigmenlasand ke
Hypertrophied sua
contraction.
HEALING IN
SPECIALISED TISSUES (p 118)
FRACTURE HEALING
Healing of fracture by callus Some clinica

considerations whether the formation depends viouslynom

upaviously
fracture is: ) traumatic (P
eday pue uonewueyuit 83LdVHD
64
MULTIPLE CHOICE QUESTIONS
1. Which of the following is first immediate vascular
A. Transient vasodilatation B. Transient respons o niyurg
C. Persistent vasodilatation
vasoconstridion
D. Persistent vasoconstriction
2. Which of the following statement is true for vascid.
acute inflammation? sCular leakinem i
A Contraction of endothelial cells affecting arterioles
mechanism
terioles is mst
B. It is mediated by histamine si
C. Direct injury to endothelial cells results in immediate trano
D. Leucocyte-mediated vascular
an early response
eakiness affects
mostly sient lek p
nulen ardn
3. All are opsonins except
IgG B. C3b
C. C5ao D. Collectin
4. All of following is true about PGI2 except:
A. Vasodilatation B. Bronchodilatation
C. Platelet aggregation D. Produced by prostacycin
syrnthae
5. Which of the following is nota feature of tuberculoid leprosy?
A. Presence of clear zone of Grenz
B. Well defined granulomatous reaction
C. Positive lepromin test
D. Paucibacillary
6. All are cardinal signs of inflammation
except:
A Pain B. Redness
C. Swelling D. Cyanosis
7. Role of L-selectin in
inflammation is:
A. Rolling B. Adhesion
C. Homingg D. Transmigration
8. Which of the
following is a C-C chemokine?
A IL-8
B. RANTES
C. Fractalkine
D. Lymphotactin
9. C3 convertase acts on:
A. C4b2b
C. C4b B. C4b2b3a
D. C3
10. Bradykinin effects include all the
A. Smooth muscle following except:
B. Vasoconstriction
contraction
C.
Increased vascular permeability
D. Pain
11. All of the
following may contribute in generating reactive
species within neutrophils for microbial killing except 0
A MPO
C. NADPH oxidase B. Fenton reaction
D. Glutathione peroxidase
ANSWERS AND BRIEF EXPLANATION
1. Answer B. Earliest
arterioles, With mild fomvascular response is of Uansienttransient vasoconstricion
vasooulished
o
35 seconds of injury, the blood
flow may De n
while with more severe ct for abo
5 minutes. This injury the vasoconstncio last
is followed
mainly the arterioles. This by persistent pro odilatation
invoMg
injury ands
change
responsible for redness and wamth obvious within half an hour o
is
2. Answer at the siteof
c acute inflammabo
B.
Contraction
Common

mechanism of increased of
endothelial most
ial cells is the usivelywhio
leakiness that affects
capillaries and arterioles remain at venules exc
release
unaffected (A.
A). It mediated by
is
the
 5
kislarrirvs, rnolkinii sarnd Ater chesrrit.st rrerdiatons irst iniyuryto erkttsfiat
adls nffete all lovels ricroasalsture (ysrnles, capillari6s ard artersles)
Ci Inctons6d pormestility rray r6stt inn eithier irirmediato sustained leaka
of delayod protonyod loukyo, Metivsted louonpos st site of iniarmrnation
rolessnso proteoly, orizyrress srid tosic onygon speies (ausing erdttelial
Iniury srid irioronsed VHsular lgskirioss, This forrn of increased vasaslar
lonkiness affects mostly veriules sarid is a latø resporise
1Answer C. IgG opsonin is tho Fo fragrnent ofirmrnunogktnulin G(IgG),
(ofresponding rocoptor on polyriorphs is Fo rocoptor for IgG called FoPI.
Cb opsorin is the broskdwn product goriorated bry activstion of omplernent
pnthway, oresporidirig rocoplor for C3b is ornplerriert recsptor 1 and 3
(CR1 and 3). C Ba is 51 anaphylotozin, Collectins are cartotydrate-birndirng
letins in the plasma which birid to bactorial csll wall, orr9sponding receptor
for collectins is C1q
4.Answer D. Endotholial cells contain enzyrme prostacycin syrthase that
forms PG12 which induces vasodilatation, bronchodilatation and inhibits
is to its stable produd, PGF1a.
platelot aggrogation. PGI2 convertod
6. Answor A, Cloar zone is seon in lepromatous leprosy in which the dermal
infiltfrate of lopra colls characteristically does not encroach upon the basal layer

of opidermis and is separated from epidermis by a subepidermal uninvolved

cloar zone
6. Answer D. Cardinal signs of inflammation described by Celsus are: i)
rubor (redness), i) tumor (swelling); ii) calor (heat); and iv) dolor (pain).To
these, fifth sign function laesa (loss of function) was later added by Galen.
7. Answer C. L-selectin (expressed on the surface of lymphocytes,
neutrophils and monocytes, also called LCAM or CD62L) is responsible
for homing of circulating leucocytes to the endothelial cells in lymph nodes.
P-selectin (expressed on platelets and cytokine-activated endothelial cells,
also called CD62P) is involved in rolling. E-selectin (synthesised by cytokine-
activated endothelial cells, also named ECAM or CD62E) is associated with
both rolling and adhesion.
8. Answer B. Four families of chemokines and their examples are as
follows: (i) C-X-C chemokine (a-chemokine) e.g. IL-8: (i) C-C chemokine
(B-chemokine) (contains two conserved C residues adjacent to each other)
e.g. MCP-1, MIP-1a, eotaxin, and RANTES (regulated and normal T cell
expressed and secreted); ii) C-chemokine (y-chemokine) e.g. lymphotactin;
and iv) CX3-C chemokin e.g. fractalkine.
9. Answer D. C3 convertase splits C3 into C3a and C3b, both of which play
significant role in inflammation.
10. Answer B. Bradykinin acts in the early stage of inflammation and its
effects include: ) smooth muscle contraction; i) vasodilatation, i) increased
vascular permeability; and iv) pain.
11. Answer D. The enzyme MPO acts on H,O, in the presence of halides
(chloride, iodide or bromide) to form hypohalous acid (HOCI, HOI, HOBr).
This is called H,O,-MPO-halide system. Fenton reaction produces OH- ions
from H,O (MPO-independent kiling). NADPH-0xidase presentin the cel
membrane of phagosome reduces oxygen to superoxide ion. Glutathione
peroxidase is scavenger of free radicals and does not generate them.

SHORT ANSWER QUESTIONS

Mention three steps involved in phagocytosis of microbes by inflammatory

cells.
2. Name five cell-derived mediators of inflammation.
3. Mention three pathways of complement activation.
4. Mention intracellular mechanisms of microbial killing and degradation.
5. Enumerate three types of inflammatory giant cells.
6, What are three components of Ghon's complex in lungs?
7. Name two types of reactional leprosy.