Inflammation is the body's response to injury or infection and is marked by redness, swelling, heat, and pain. It involves both vascular and cellular events. The vascular events include vasodilation, increased blood flow, and increased vascular permeability, allowing fluid protein exudation. The cellular events involve leukocyte migration from blood vessels to infected/injured tissues, mainly neutrophils in acute inflammation. This document discusses the history, definitions, signs, and components of the acute inflammatory response.
3. Components of acute and chronic inflammatory response
Acute inflammation
Vascular events
Hemodynamic changes
Altered vascular permeability
Cellular events
Exudation of leucocytes
Phagocytosis
3
4. INTRODUCTION
Inflammation is defined as the local response of living
mammalian tissues to injury due to any agent.
Body defense reaction – eliminate or limit the spread of
injurious agent.
4
Entrapment Phagocytosis
Hemocytes
Neutralization (hypertrophy
of cell/ organelle)
Invertebrates and single
celled organisms
5. Historical Highlights
Clinical features of inflammation
Described in Egyptian papyrus( dated around 3000 BC)
Celsus
Roman writer of 1st century AD
First listed the 4 cardinal signs of inflammation.
5
6. Functio laesa – Rudolf Virchow – 19th century
Fifth clinical sign
Scottish surgeon John Hunter (1793)
‘’Inflammation is not a disease, but a non-specific response
that has a salutary effect on its host ‘’
6
7. Julius Cohnheim (1839-1884)
First used the microscope to observe inflamed blood
vessels in thin, transparent membranes, such as in the
mesentry and tongue of frog.
Noted the initial changes in blood flow, the subsequent
oedema caused by increased vascular permeability and
characteristic leucocytic migration.
7
8. Elie Metchnikoff (1880)
Russian biologist
Discovered the process of phagocytosis
By observing the ingestion of rose thorns by amebocytes of
starfish larvae and of bacteria by mammalian leucocytes.
8
9. Sir Thomas Lewis
Studied the inflammatory response in skin
Described triple response (1924)
Chemical substances (histamine), mediate the vascular
changes of inflammation
9
10. A local response to cellular injury that is
marked by capillary dilatation, leucocytic
infilteration, swelling, redness, heat and
pain serving as a mechanism initiating
the elimination of noxious agents and of
damaged tissue - defined by Merriam
Webster Medical Dictionary
DEFINITIONS
10
11. A protective response
intended to eliminate the
initial cause of cell injury as
well as the necrotic cells and
tissues resulting from
original insult – ROBBIN’s
11
14. INFLAMMATION: Protective response by the body to variety
of etiologic agents
INFECTION: Invasion into the body by harmful microbes and
their resultant ill-effects by toxins
2 basic processes with some overlapping
early inflammatory response
later followed by healing
14
15. Sometimes it causes considerable harm to the body as well
anaphylaxis to bites by insects or reptiles, drugs, toxins
atherosclerosis
15
17.
INFLAMMATION INFECTION
Body's general response to disease and
may occur secondary to infection, tumors,
physical trauma or other conditions both
local and widespread. Inflammation is not
synonymous with infection
Infection almost always causes
inflammation
Inflammation is very often present in the
absence of infection
Infection involves colonization of body
tissues by microorganisms such as
bacteria, viruses, fungi or even the newest
form of infectious organism discovered,
"prions
Inflammation is simply the bodies
response to biological insult, with
infection being just one type of insult.
17
18. “Is it a protective or defensive
process?? Why??”
It removes or destroys causative agents
Repairs tissue damage
Inactivate toxins
Prepare tissue or organ for healing & repair
18
20. Cause of Inflammation
20
Infective agents bacteria, viruses and their toxins, fungi,
parasites
Immunological
agents
cell-mediated and antigen antibody
reactions
Chemical agents organic and inorganic poisons
Physical agents heat, cold, radiation, mechanical trauma
Inert materials foreign bodies
21. TYPES OF INFLAMMATION
Acute versus chronic inflammation are distinguished by the
duration and the type of infiltrating inflammatory cells
Acute
Inflammation
INFLAMMATION
Chronic
inflammation
21
22. 22
Acute inflammation Chronic inflammation
Rapid in onset Insidious onset
Short duration , lasts from few
minutes to as long as few days
Longer duration, lasts for several
days to years
Represents the early body reaction
- followed by healing
Causative agent of acute
inflammation persists for a long
time
Fluid and plasma protein exudation
(edema)
Vascular proliferation and fibrosis
Prominent neutrophilic infiltration Lymphocytic and macrophagic
infiltration
23. Another variant of chronic inflammation, CHRONIC
ACTIVE INFLAMMATION
Stimulus is such that it induces chronic inflammation
from the beginning
23
27. ACUTE INFLAMMATION
27
A rapid response to injury or
microbes and other foreign
substances that is designed to
deliver leucocytes and plasma
proteins to sites of injury
28. The main features :
Accumulation of fluid and plasma at the affected site
Intravascular activation of platelets
Polymorphonuclear neutrophils as inflammatory cells.
28
29. VASCULAR EVENTS:-
alterations in vessel
caliber resulting in
increased blood flow
(vasodilation) and
structural changes that
permit plasma proteins to
leave the circulation
(increased vascular
permeability)
29
30. 30
CELLULAR EVENTS:- emigration
of the leukocytes from the
microcirculation and
accumulation in the focus of
injury (cellular recruitment and
activation).
This 2 events are followed intermittently by release of mediators
of acute inflammation
The principal leukocytes in acute inflammation are
neutrophils (polymorphonuclear leukocytes).
31. VASCULAR EVENTS
• Alteration in the microvasculature (arteriole, capillaries
and venules) – earliest response to tissue injury.
• These alterations include:
Hemodynamic changes
Altered vascular permeability
31
32. Hemodynamic changes
TRANSIENT VASOCONSTRICTION :
immediate vascular response irrespective of the type of
injury
mainly arterioles
Mild injury→ 3-5 seconds
Severe injury → 5 minutes
32
33. PERSISTENT PROGRESSIVE VASODILATATION :
mainly arterioles, (to a lesser extent →venules and capillaries)
Change is obvious within half an hour of injury
Vasodilatation → increased blood volume in microvascular bed
of the area →
Responsible for redness and warmth at the site of acute
inflammation
Induced by the action of several mediators, notably histamine
and nitric oxide
33
34. 34
Progressive vasodilatation
↓
elevate the local hydrostatic pressure
↓
transudation of fluid (protein-rich fluid) into the
extravascular tissues
↓
Responsible for swelling at the local site of acute
inflammation
35. As the microvasculature becomes more permeable
↓
This causes the red blood cells to become more
concentrated
↓
thereby increasing blood viscosity
↓
Slowing or stasis of microcirculation
35
36. LEUCOCYTIC MARGINATION (EMIGRATION)
Peripheral orientation of leucocytes (mainly
neutrophils) along the vascular endothelium
Stick to the vascular endothelium briefly
Move and migrate through the gaps between the
endothelial cells and into extravascular space
36
37. THE MAJOR LOCAL MANIFESTATION OF ACUTE INFLAMMATION
COMPARED TO NORMAL
37
38. LEWIS EXPERIMENT
The features of haemodynamic changes in inflammation
are best demonstrated by lewis experiment.
Sir Thomas Lewis (1924) induced the changes in the skin
of inner aspect of forearm by firm stroking with a blunt
point.
The reaction so elicited is known as TRIPLE RESPONSE or
RED LINE RESPONSE.
38
40. RED LINE – Appears within a few seconds following stroking --- due
to vasodilatation of capillaries and venules.
FLARE – Bright reddish appearence or flush surrounding the red line-
-- due to vasodilatation of adjacent arterioles.
WHEAL - The swelling or oedema of the surrounding skin occurring
due to transudation of fluid into the extravascular space.
These features, thus, elicit the classical signs of inflammation -
REDNESS, HEAT, SWELLING & PAIN.
40
41. ALTERED VASCULAR PERMEABILITY
A hallmark of acute inflammation → ↑sed vascular permeability
↓
Escape of protein rich fluid into extravascular tissue
Reduces the intravascular osmotic pressure
41
42. 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, the escape of fluid is due to
vasodilatation and consequent elevation in hydrostatic
pressure.
This is transudate in nature.
42
43. But, subsequently, the characteristic inflammatory
oedema, appears by increased vascular permeability of
microcirculation – exudate
43
45. EXUDATE / TRANSUDATE
EXUDATE
Result of inflammation
Vascular permeability
High protein content
specific gravity >1.020
TRANSUDATE
Result of hydrostatic or
osmotic imbalance
Ultra filtrate of plasma
Low protein content
Specific gravity < 1.015
45
46. STARLING’S HYPOTHESIS
The appearance of inflammatory oedema due to
increased vascular permeability of microvascular bed is
explained on the basis of Starling’s hypothesis.
46
47. Forces that cause outward movement of fluid from
microcirculation→ intravascular hydrostastic pressure
and colloid osmotic pressure of interstitial fluid
Forces that cause inward movement of interstitial fluid
into circulation→ intravascular colloid osmotic pressure
and hydrostatic pressure of interstitial fluid
47
48. Whatever fluid is left in the
interstitial compartment is
drained away by
lymphatics………….thus no
oedema results normally.
48
49. In inflamed tissue,
Intravascular colloid osmotic pressure ↓se
Osmotic pressure of interstitial fluid ↑se
Result in excessive outward flow of fluid
into the interstitial tissue , which is
exudative inflammatory oedema.
49
50. MECHANISMS OF INCREASED
VASCULAR PERMEABILITY
1. Contraction of endothelial cells.
2. Retraction of endothelial cells
3. Direct injury to endothelial cells
4. Endothelial injury mediated by leucocytes
5. Transcytosis
6. Leakiness and neo-vascularization
50
52. 1.Contraction of endothelial
cells
Affects venules exclusively
Most common mechanism of ↑sed
leakiness
Endothelial cells develop temporary gaps
between them, due to contraction resulting
in vascular leakiness.
52
53. Mediated by the release of histamine, bradykinin and
other chemical mediators.
Response begins immediately after injury
Short duration (15-30 minutes)
Eg: immediate transient leakage in mild thermal injury of
skin of forearm.
53
54. 2.Retraction of endothelial
cells
Structural re-organisation of the cytoskeleton of endothelial
cells
Cause reversible retraction at the intercellular junctions.
Venules
Mediated by cytokines such as interleukin-1 (IL-1) and
tumour necrosis factor (TNF)-α.
Onset of response→4-6hrs after injury
Last for 2-4 hrs or more (delayed/prolonged leakage)
54
55. 3.Direct injury to endothelial
cells
Causes cell necrosis and appearance of physical gaps at the site of
detached endothelial cells.
Process of thrombosis is initiated at the site of damaged
endothelial cells.
Affects all levels of microvasculature ( arterioles, venules and
capillaries)
55
56. Either appear immediately after injury and last for several
hours or days (immediate sustained leakage) eg: severe
bacterial infections
Or delay of 2-12 hours and last for hours or days (delayed
prolonged leakage) – may occur following moderate
thermal injury and radiation injury
56
57. 4.Endothelial injury mediated by
leucocytes
Activated by adherence of leucocytes to the endothelium at
the site of inflammation.
Activation of leucocytes → release proteolytic enzymes and
toxic oxygen species
↓
Cause endothelial injury and increased vascular leakiness.
57
58. Affects mostly venules
Late response
Venules, pulmonary and glomerular capillaries (in these
areas, leucocytes adhere for longer periods to the
endothelium.
58
59. 5.Increased Transcytosis
Increased transfer of fluid and proteins thr’ the
endothelial cell wall – called transcytosis
Occurs across channels consisting of clusters of
interconnected, uncoated vesicles and vacoules called
the vesiculovacoular organelle
Vascular endothelial growth factor (VEGF)appear to
cause vascular leakage
59
60. 6.Leakiness and
Neovascularisation
New vessel sprouts remain leaky until the endothelial cells
mature and form intercellular junctions.
During repair, endothelial cells proliferate and form new
blood vessels →ANGIOGENESIS
Newly formed capillaries under the influence of vascular
endothelial growth factor (VEGF)
.
60
61. All these factors account for oedema that is characteristic of
the early phase of healing that follow inflammation
61
63. Leucocyte adhesion and transmigration are largely
regulated by the binding of complementary adhesion
molecules on the leucocyte and endothelial surfaces, and
chemical mediators - chemoattractants and cytokines –
affect these processes by ,modulating the surface
expression or avidity of such adhesion molecules.
63
64. I. Exudation of leucocytes
The escape of leucocytes from the lumen of
microvasculature to the interstitial tissue - most important
of inflammatory response.
In acute inflammation , PMN neutrophils comprise the 1st
line of body defense, followed later by monocytes and
macrophages.
64
65. The changes leading to migration of leucocytes are as follows:
1. Changes in the formed elements of blood.
2. Rolling and adhesion
3. Emigration
4. Chemotaxis
65
66. 1. Changes In The Formed Elements Of Blood
In normal axial flow………..Central stream of cells comprised by leucocytes
and RBCs and peripheral cell free layer of plasma close to vessel wall.
Due to slowing or stasis, the central stream of cells widens and peripheral
plasma zone becomes narrower because of loss of plasma by exudation.
This phenomenon is known as margination.
As a result of this redistribution, the neutrophils of the central column come
close to the vessel wall , known as pavementing
66
69. 2. Rolling And Adhesion
Peripherally marginated and pavemented neutrophils slowly
roll over the endothelial cells lining the vessel wall (rolling
phase).
Followed by, transient bond between the leucocytes and
endothelial cells becoming firmer (adhesion phase).
69
70. Rolling And Adhesion
70
The following molecules bring about rolling and adhesion phases
– Selectins
– Integrins
– Immunoglobulin gene superfamily adhesion molecule
71. 3. Emigration
After sticking of neutrophils to endothelium, the former move along the
endothelial surface till a suitable site between the endothelial cells is found
, where the neutrophils throw out cytoplasmic pseudopods
Subsequently, the neutrophils lodged b/w the endothelial cells and
basement membrane ,cross the basement membrane by damaging it locally
with secreted collagenases and escape out into the extravascular space
→EMIGRATION
The damaged basement membrane is repaired almost immediately.
71
73. DIAPEDESIS
escape of red cells through gaps between the endothelial
cells
Passive phenomenon
RBC’s being forced out by raised hydrostatic pressure or
may escape thr’ the endothelial defects left after emigration
of leucocytes.
Gives haemorrhagic appearance to the inflammatory
exudate.
73
74. CHEMOTAXIS
The chemotactic factor-mediated transmigration of
leucocytes after crossing several barriers (endothelium,
basement membrane, perivascular myofibroblasts and
matrix) to reach the interstitial tissues → chemotaxis
The concept of chemotaxis is well illustrated by Boyden’s
chamber experiment.
74
76. Boyden’s Chamber Experiment
A millipore filter (3 um pore size) seperates the suspension
of leucocytes from the test solution in tissue culture
chamber.
If the test solution contains chemotactic agents, the
leucocytes migrate thr’ the pores of filter towards the
chemotactic agent.
76
78. Potent chemotactic substances or
chemokines for neutrophils
Leukotriene B4 (LT-B4) – product of lipoxygenase pathway
of arachidonic acid metabolites
Components of complement system (C5a and C3a in
particular)
Cytokines (Interleukins, in particular IL-8)
Soluble bacterial products (eg: formulated peptides)
78
79. II. PHAGOCYTOSIS
The process of engulfment of solid particulate material by the
cells.
Cells performing this function - phagocytes
2 main types of phagocytic cells
Polymorphonuclear neutrophils (PMNs) : appear early in acute
inflammatory response, also known as microphages
Macrophages : Circulating monocytes and fixed tissue
mononuclear phagocytes
79
80. These phagocytic cells on reaching the tissue spaces
releases proteolytic enzymes - lysozyme, protease,
collagenase, elastase, lipase, proteinase, gelatinase and acid
hydrolases
These enzymes degrade collagen and extracellular matrix.
80
81. The microbe undergoes the process of phagocytosis in
following 3 steps :
I. Recognition and attachment
II. Engulfment
III. Killing and degradation
81
82. 1. Recognition and Attachment
Phagocytosis is initiated by the expression of surface receptors
on macrophages (mannose receptor and scavenger receptor) –
which recognize microorganisms.
Its further enhanced when the microbes are coated with
specific proteins, opsonins, from serum or they get opsonized.
Opsonins establish a bond between bacteria and the cell
membrane of phagocytic cell
82
83. Main opsonins present in serum and their corresponding receptors on
the surface of phagocytic cells (PMN’s or macrophages) :
IgG opsonin The Fc fragment of IgG.
Naturally occurring antibody in
serum that coats the bacteria.
C3b opsonin Fragment generated by activation
of complement pathway.
Strongly chemotactic for attracting
PMN’s to bacteria.
Lectins Carbohydrate-binding proteins in
the plasma which bind to bacterial
cell wall.
83
84. 84
Stages in phagocytosis of a foreign particle:
A. Opsonization of the particle
B. Pseudopod engulfing the opsonized particle
C. Incorporation within the cell (phagocytic vacuole) and degranulation
D. Phagolysosome formation after fusion of lysosome of the cell
A DCB
85. 2. Engulfment
The opsonized particle bound to the surface of phagocyte is
ready to be engulfed.
This is accomplished by formation of cytoplasmic
pseudopods around the particle due to activation of actin
filaments beneath cell wall, enveloping it in a phagocytic
vacuole.
85
86. Eventually, plasma membrane enclosing the particle
breaks from the cell surface, so that membrane lined
phagocytic vacuole or phagosome lies internalized and free
in the cell cytoplasm
The phagosome fuses with one or more lysosomes of cell
and form bigger vacoule – phagolysosome.
86
87. 3. Killing and Degradation
The ultimate step in the elimination of infectious agents and
necrotic cells is their killing and degradation with neutrophils and
macrophages, which occur most efficiently after activation of
phagocytes.
Microbial killing is accomplished largely by oxygen- dependent
mechanisms
87
88. After being killed by antibacterial substances , they are
further degraded by hydrolytic enzymes
However, this mechanism fails to kill and degrade some
bacteria like tubercle bacilli.
88
92. Killing and Degradation
The following mechanism facilitate the process:
Extracellular mechanisms Intracellular mechanisms
Disposal of microorganisms
92
93. Disposal of Microorganisms
A. Intracellular mechanisms
i. Oxidative bactericidal mechanism by oxygen free
radicals
MPO-dependent
MPO-independent
ii. Oxidative bactericidal mechanism by lysosomal granules
iii. Non-oxidative bactericidal mechanism
* Kill microbes by oxidative mechanism and less often non-oxidative pathways
93
97. 97
NADPH oxidase present in the cell membrane of
phagosome reduces oxygen to superoxide ion (O’₂)
Superoxide is subsequently converted into H₂O₂ which has
bactericidal properties.
2O’ ₂ + 2H⁺ → H₂O₂
98. This type of bactericidal activity is carried out either via
enzyme myeloperoxidase (MPO) present in the azurophillic
granules of neutrophils and monocytes, or independent of
enzyme MPO
98
99. MPO Dependent Killings
The enzyme MPO acts on H₂O₂ in the presence of halides
to form hypohalous acid (HOCl, HOI, HOBr)
This is called H₂O₂-MPO-halide system
More potent antibacterial system in polymorphs than H₂O₂
alone
99
H₂O₂-MPO-halide system
100. MPO Independent Killings
Mature macrophages lack the enzyme MPO
Carry out bactericidal activity by producing OH⁻ ions and
superoxide singlet oxygen (O’) from H₂O₂
in the presence of O’ ₂ (Haber-Weiss reaction)
or in the presence of Fe++ (Fenton reaction)
100
101. Reactive oxygen metabolites are particularly useful in
eliminating microbial organisms that grow within
phagocytes.
Eg: M. Tuberculosis, Histoplasma capsulatum
101
102. ii. Oxidative bactericidal
mechanism by lysosomal granules
Preformed granule-stored products of neutrophils and
macrophages are discharged or secreted into the phagosome
and the extracellular environment.
Progressive degranulation of neutrophils and macrophages
along with oxygen free radicals degrades proteins i.e: induces
proteolysis.
102
103. iii. Non-oxidative Bactericidal
Mechanism
Some agents released from the granules of phagocytic cells
do not require oxygen for bactericidal activity
These include:
a) Granules :
some of liberated lysosomal granules donot kill by oxidative
damage,
but cause lysis of within phagosome.
eg: lysosomal hydrolases, permeability increasing factors,
cationic proteins (defensins), lipases, proteases, DNAases.
103
104. b) Nitric oxide :
NO reactive free radicals similar to oxygen free radicals
Formed by nitric oxide synthase
produced by endothelial cells as well as by activated
macrophages
potent mechanism of microbial killing
104
105. EXTRACELLULAR MECHANISMS
1. Granules – Degranulation of macrophages and
neutrophils
2. Immune mechanisms
immune-mediated lysis of microbes takes place outside
the cells
by mechanisms of cytolysis, antibody-mediated lysis and
by cell-mediated cytotoxicity
105
107. RESOLUTION
All inflammatory reactions, once they have succeeded in
neutralizing and eliminating the injurious stimulus, should
end with restoration of the site of acute inflammation to
normal – Resolution
Usual outcome when injury is limited or short-lived or
when cellular changes are reversible
Involves neutralization or spontaneous decay of chemical
mediators
108
108. HEALING
Healing by connective tissue replacement (fibrosis)
Occurs after substantial tissue destruction, so there is no
tissue regeneration
But when tissue loss is superficial, it is restored by
regeneration
109
109. SUPPURATION
When the pyogenic bacteria
causing acute inflammation
result in severe tissue
necrosis, the process
progresses to suppuration.
Initially, there is intense
neutrophillic infilteration.
110
110. Subsequently, mixture of neutrophils, bacteria,fragments
of necrotic tissue, cell debris and fibrin comprise pus which
is contained in a cavity to form an abscess.
The abscess, if not drained, may get organized by dense
fibrous tissue, and in time, get calcified.
111
111. CHRONIC INFLAMMATION
Persisting or recurrent acute inflammation may progress to
chronic inflammation in which the processes of
inflammation and healing proceed side by side.
Angiogenesis
Mononuclear cell infiterate
Fibrosis (scar)
112
112. SYSTEMIC EFFECTS OF ACUTE
INFLAMMATION
Fever : due to bacteriemia
leucocytosis : 15000-20000/ul
Bacterial infections – neutrophilia
Viral infections – lymphocytosis
Parasitis infections – eosinophilia
Lymphangitis-lymphadenitis
Shock (in severe cases)
113
114. CHEMICAL MEDIATORS OF INFLAMMATION
‘’permeability factors’’ or ‘’endogenous mediators of
increased vascular permeability”
Any messenger that acts on blood vessels, inflammatory
cells, or other cells to contribute to an inflammatory response
Responsible for vascular and cellular events
Knowledge of this mediators – basis of anti-inflammatory
drugs
115
118. Production of active mediators is triggered by microbial
products or by host proteins, such as the proteins of the
complement, kinin, and coagulation systems, that are
themselves activated by microbes and damaged tissues.
119
119. Most mediators perform their
biologic activity by
Binding to specific receptors on target cells
(It may be one or a very few targets, or multiple)
Direct enzymatic activities (eg: lysosomal proteases)
Mediate oxidative damage (eg: reactive oxygen and
nitrogen intermediates)
120
120. Some mediators may stimulate target cells to release
secondary effector molecules
But these secondary effector molecules may also :
Control the response and tightly regulated
amplify a particular response
opposing effects
121
121. 122
Once activated and released from the cell, most of
these mediators are short lived
quickly decay (eg: arachidonic acid metabolites) or
inactivated by enzymes (eg: kininase inactivates
bradykinin)
Scavenged (eg: antioxidants scavenge toxic oxygen
metabolites)
Inhibited (eg: Complement-inhibitory proteins
123. 1. Vasoactive Amines
Stored as preformed molecules in mast cells or early
inflammatory cells
1st mediators to be released during inflammation.
Histamine
Serotonin – 5-hydroxytryptamine
Neuropeptides
124
124. Histamine
Widely distributed in many cell types
Richest source : mast cells adjacent to blood vessels
circulating basophils and platelets
Main action of histamine:
Vasodilatation, Increased vascular (venular) permeability,
Itching and pain
125
125. Preformed histamine present in mast cell granules
Released by mast cell degranulation in response to a variety of stimuli
i. physical injury (trauma, cold, heat)
ii. immune reactions involving binding of IgE antibodies to Fc
receptors on mast cells
iii. fragments of complement (Anaphylatoxins) → C3a and C5a
iv. histamine-releasing proteins → derived from Leukocytes
v. Cytokines (IL-1,IL-8)
126
126. Serotonin
5-hydroxytryptamine
preformed vasoactive mediator
Actions similar to those of histamine, but less potent
Present in platelets and enterochromaffin cells
Increased vascular permeability
127
127. Neuropeptides
Eg: substance P , neurokinin A, vasoactive intestinal peptide
(VIP), somatostatin
These small peptides are released by central and peripheral
nervous system.
Major proinflammatory actions include:
Increased vascular permeability
Transmission of pain stimuli
Mast cell degranulation
128
128. 2. ARACHIDONIC ACID (AA)
METABOLITES
Also known as EICOSANOIDS
Constituent of phospholipid cell membrane
AA is released from these phospholipids via cellular
phospholipases
that have been activated by mechanical, chemical, physical
stimuli, or by inflammatory mediators such as C5a.
129
129. Arachidonic acid metabolites
contribute to inflammation by:
i. Increasing capillary permeability
ii. Inducing local vasodilatation and thus redness
iii. Promoting infilteration of inflammatory cells
iv. Production of tissue injuring oxygen free radicals during
the synthesis of PGs and LTs
v. Producing inflammation associated hyperalgesia
(Increased pain)
131
130. 3. LYSOSOMAL COMPONENTS
Inflammatory cells like neutrophils and monocytes contain
lysosomal granules.
Its of 2 types :
Granules of neutrophils
Granules of monocytes and tissue macrophages
132
131. GRANULES OF NEUTROPHILS
I. Primary or azurophil : myeloperoxidase, acid hydrolases,
acid phosphatase, lysozyme, defensin (cationic protein),
phospholipase, cathepsin G, elastase, and protease
II. Secondary or specific : alkaline phosphatase, lactoferrin,
gelatinase, collagenase, lysozyme, vitamin-B12 binding
proteins, plasminogen activator
III. Tertiary : gelatinase and acid hydrolases
133
132. Granules of monocytes and tissue macrophages
acid proteases, collagenase, elastase and plasminogen
activator
more active in chronic inflammation
134
133. 4. PLATELET ACTIVATING FACTOR (PAF)
Released from IgE- sensitized basophils or mast cells, other
leucocytes, endothelium and platelets.
Functions of PAF
1. ↑sed vascular permeability
2. Inducing vasodilation
3. vasoconstriction and bronchoconstriction(low conc:)
4. Adhesion of leukocytes to endothelium
5. chemotaxis
135
134. 5. CYTOKINES
polypeptide substances produced by activated lymphocytes
(lymphokines) and activated monocytes (monokines)
Major cytokines in acute inflammation
TNF- α and IL-1 → formed by activated macrophages
TNF-β and Interferon (IFN-γ) → formed by activated T-cells
Chemokines - a group of chemoattractant cytokines
IL-8 → released from activated macrophages
PF-4 (Platelet factor-4) → released from activated platelets
136
135. Actions of various cytokines
137
Interferon (IFN-γIL-1, TNF- α and TNF- β
Activation of macrophages
and neutrophils
Associated with synthesis
of nitric oxide synthase
↑sed leucocytic adherence
Thrombogenecity
elaboration of other cytokines
fibroblastic proliferation
acute phase reactions
136. 6.Reactive Oxygen Species
synthesized via the NADPH oxidase – from neutrophils and
macrophages
by microbes, immune complexes, cytokines, and a variety
of other inflammatory stimuli
Within lysosomes - destroy phagocytosed microbes and
necrotic cells
low levels – increase chemokine, cytokine, and adhesion
molecule expression – amplifying the cascade of
inflammatory mediators
138
137. High levels - tissue injury by several mechanisms
1. endothelial damage, with thrombosis and increased
permeability
2. protease activation and antiprotease inactivation, with a
net increase in breakdown of the ECM
3. direct injury to other cell types
139
138. 7. Nitric Oxide
short-lived, soluble, free-radical gas
formed by activated macrophages during the oxidation of
arginine by the action of enzyme, NO synthase (NOS)
Three isoforms of NOS
Type I (nNOS) – neuronal, no role in inflammation
Type II (iNOS) – induced by chemical mediators,
macrophages and endothelial cells
Type III (eNOS) - primarily (but not exclusively) within
endothelium
140
139. NO plays many roles in inflammation including
relaxation of vascular smooth muscle (vasodilation)
antagonism of all stages of platelet activation (adhesion,
aggregation, and degranulation)
reduction of leukocyte recruitment at inflammatory sites
action as a microbicidal (cytotoxic) agent (with or without
superoxide radicals) in activated macrophages
141
140. Plasma-protein-derived
mediators
Inactive precursors that are activated at the site of
inflammation by the action of enzyme
Circulating proteins of three interrelated systems - the
complement, kinin, clotting and fibrinolytic systems
Each of these systems has its inhibitors and accelerators
in plasma with negative and positive feedback
mechanisms respectively
Hageman factor (factor XII) of clotting system plays a
key role in interactions of the four systems
142
141. Hageman Factor (Factor XII)
Protein synthesized by the liver
Initiates four systems involved in the inflammatory response
Kinin system - vasoactive kinins
Clotting system - inducing the activation of
thrombin,fibrinopeptides, and factor X
Fibrinolytic system - plasmin and inactivating thrombin
Complement system - anaphylatoxins c3a and c5a
Gets activated - collagen, basement membrane, or activated
platelets
143
142. 1. Clotting System
Factor XIIa initiates the proteolytic cascade resulting in the
formation of fibrinogen, which is acted upon by thrombin to
form fibrin and fibrinopeptides.
144
144. Functions of thrombin
Cleaves circulating soluble fibrinogen to generate an
insoluble fibrin clot
Fibrinopeptides
Increase vascular permeability
Chemotaxis of leukocytes
In inflammation, binding of thrombin to the receptors on
endothelial cells - activation and enhanced leukocyte
adhesion
146
145. 2.Fibrinolytic System
Hageman factor induces clotting system and fibrinolytic
system concurrently
Limit clotting by cleaving fibrin - solubilizing the fibrin clot
In absence of this – even minor injury could lead to
coagulation of entire vasculature
Plasminogen activator - released from endothelium,
leukocytes, and other tissues) and kallikrein from kinin
system
→ Cleave plasminogen, a plasma protein
→ further forms PLASMIN
147
146. Plasmin
Multifunctional protease that cleaves fibrin
Cleaves the C3 complement protein → production of C3a
Activate Hageman factor → amplify the entire set of
responses
148
148. Bradykinin
1. short-lived - rapidly degraded by kininases present in
plasma and tissues
2. Slow contraction of smooth muscle
3. acts in the early stage of inflammation: – vasodilatation,
increased vascular permeability, pain
150
149. 4. Complement System
Important role in host defense (immunity) and inflammation
Consists of plasma proteins (C1 – C9) – activated at the sites of
inflammation
Most of the complement proteins and glycoproteins are produced in
the liver in an inactive form (zymogen), activation is induced by
proteolytic clevage
Contribute to the inflammatory response by increasing vascular
permeability and leukocyte chemotaxis
151
152. ◦ The actions of activated complement system in
inflammation are as under:
C3a, C5a, C4a (anaphylatoxins) - activate mast cells and
basophils to release of histamine
C3b - an opsonin
C5a - chemotactic for leucocytes
Membrane attack complex (MAC)
C5b-C9 - a lipid dissolving agent and causes holes in the
phospholipid membrane of the cell
156
154. CHRONIC INFLAMMATION
158
Inflammation of prolonged
duration (weeks to months
to years) in which active
inflammation, tissue
injury, and healing
proceed simultaneously.
155. MORPHOLOGIC FEATURES
Infilteration with mononuclear cells - macrophages,
lymphocytes, and plasma cells
Tissue destruction, induced by the persistent offending
agent or by the inflammatory cells.
Healing by connective tissue replacement of damaged
tissue, accomplished by angiogenesis and, in particular
fibrosis
159
156. CAUSES OF CHRONIC INFLAMMATION
Following acute inflammation – persistence of the injurious
agent or because of interference with the normal process of
healing
e.g. in osteomyelitis
pneumonia terminating in lung abscess
160
157. CAUSES OF CHRONIC INFLAMMATION
Recurrent attacks of acute inflammation – repeated bouts of acute
inflammation culminate in chronicity of the process
Eg: Recurrent urinary tract infection - chronic pyelonephritis
Repeated acute infection of gall bladder - chronic cholecystitis
161
158. CAUSES OF CHRONIC
INFLAMMATION
Chronic inflammation starting de novo – low pathogenicity is
chronic from the beginning
Eg : infection with Mycobacterium tuberculosis
Treponema pallidum
162
160. Macrophages
Dominant cells of chronic inflammation
Derived from circulating blood monocytes and tissue
macrophages.
Component of Mononuclear- phagocyte system (Also
known as Reticulo-endothelial system)
164
161. Role of Macrophages in
Inflammation
Phagocytosis (cell eating) & Pinocytosis ( cell drinking)
Macrophages on activation by lymphokines released by
T lymphocytes or by non-immunologic stimuli elaborate a
variety of biologically active substances such as:
Proteases (collagenase and elastase) → degrade collagen
and elastic tissue.
Plasminogen activator → activates fibrinolytic system
165
162. 166
Products of complement
Coagulation factors (factor V and thromboplastin) → convert
fibrinogen to fibrin
Chemotactic agents for other leucocytes
Metabolites of arachidonic acid
Growth promoting factors ( fibroblasts, blood vessels,
granulocytes)
Cytokines (IL-1, TNF-α)
Oxygen derived free radicals
163. 167
Tissue Macrophages scattered in connective tissue includes:
liver (Kupffer cells)
Spleen and lymph nodes (sinus histiocytes)
central nervous system (microglial cells)
lungs (alveolar macrophages)-----Type II pneumocytes
Placenta (Hoffbauer cells)
bone (Osteoclasts)
germinal centre of lymph nodes (Tingible body cells)
Skin (Langerhan’s cells/ dendritic histiocytes )
Glomerulus (Mesangial cells )
164. Lymphocytes
Mobilized in antibody-mediated and cell-mediated immune
reactions
T and B lymphocytes migrate - inflammatory sites –
chemokines
Lymphocytes and macrophages interact in a bidirectional way
Important role in chronic inflammation
B cells : antibody production
T cells: delayed hypersensitivity,
cytotoxicity
168
165. Plasma cells
Develop from activated B lymphocytes
Produce antibody directed either against persistent antigen
in the inflammatory site or against altered tissue
components.
Larger than lymphocytes
More abundant cytoplasm
Eccentric nucleus with cartwheel
Pattern of chromatin
169
166. Eosinophils
Inflammatory sites around parasitic infections or as
part of immune reactions mediated by IgE
Associated with allergies
Recruitment of eosinophil involves extravasation from
the blood and their migration into tissues by
chemokines
Specific chemokines in recruitment of eosinophil –
eotaxin
170
167. Granules contain major basic protein - highly
charged cationic protein – toxic to parasites
also causes epithelial cell necrosis
contribute to tissue damage in immune reactions
171
168. Mast cells
Sentinel (watch) cells widely distributed in connective
tissues throughout the body
Participate in both acute and chronic inflammatory
responses
Elaborate cytokines such as TNF and chemokines
atopic individuals - individuals prone to allergic reactions
Mast cells Armed with IgE antibody
As the environmental antigens enters – It releases
histamines and AA metabolites – anaphylactic shock
172
169. SYSTEMIC EFFECTS OF
CHRONIC INFLAMMATION
Also known as acute-phase reaction
Fever : infectious form of inflammation
Anaemia : accompanied by anaemia of varying degree
leucocytosis but generally there is relative lymphocytosis in
these cases.
ESR : elevated
Amyloidosis : develop secondary systemic (AA) amyloidosis.
173
171. REFERENCES
1. Robbinson's Basic Pathology 8 Edition
2. Color Atlas Of Pathology
3. Essential Pathology Harsh Mohan. Sugandha Mohan.
6th Edition
4. Textbook Of Oral Pathology Shaffer, William
5. Oral And Maxillofacial Pathology Neville, Brad W
6. Textbook Of Microbiology Ananthanarayanan And
Paniker
7. Textbook Of Biochemistry. N.Vasudevan
8. Textbook Of Medical Physiology. Guyton Arthur And
John L Hall
175
172. 176
1. Michio nagata Immune-mediated glomerular injury.
Journal of Pediatric Nephrology 2009(6); 1:703-41
2. Chen HC. Boyden chamber assay Methods Mol Biol. 2005
3. Lentsch AB,Ward PA:Regulation of inflammatory vascular
damage. J Pathol 190:343,2000
4. Bates DO,et al: Regulation of microvascular permeability
by vascular endothelial growth factors. J A nat
200:581,2002
5. Nathan CF: Points of control in inflammation. Nature
420:846,2002
6. Kaplan AP, et al: The intrinsic coagulation/kinin-forming
cascade: assembly in plasma and cell surfaces in
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