2. CONTENTS
DEFINITION
TYPES OF INFLAMMATION
COMPONENTS OF INFLAMMATION
HISTORICAL HIGHLIGHTS
ACUTE INFLAMMATION
A. DEFINITION
B. STIMULI FOR ACUTE INFLAMMATION
C. VASCULAR CHANGES
D. CELLULAR EVENTS
a. margination & rolling
b. adhesion & transmigration
c. chemotaxis &activation
d. phagocytosis °ranulation
e. leukocyte induced tissue injury
f. defects in leukocyte function
3. CHEMICAL MEDIATORS OF INFLAMMATION
OUTCOMES OF ACUTE INFLAMMATION
MORPHOLOGIC PATTERNS OFACUTE
INFLAMMATION
CHRONIC INFLAMMATION
SYSTEMIC EFFECTS OF INFLAMMATION
CONSEQUENCES OF DEFECTIVE OR EXCESSIVE
INFLAMMATION
4. DEFINITION
Inflammation is a complex reaction to injurious
agents such as microbes and damaged, usually necrotic,
cells that consists of vascular responses ,migration and
activation of leukocytes, and systemic reactions.
Kumar,Abbas,Fausto:Robbins and Cotran Pathological
basis of disease.Pennysilvenya,Elsevier,1999
6. ACUTE INFLAMMATION
Is the immediate & early response to injury.
Is of relatively short duration.
Due to neutrophilic leukocytic accumulation.
CHRONIC INFLAMMATION
Is of longer duration in which active inflammation
tissue injury & healing proceed simultaneously.
Manifested by influx of lymphocytes & macrophages.
7. COMPONENTS OF INFLAMMATION
The inflammatory response consists of two main
components-
A. a vascular reaction
B. a cellular reaction
8. HISTORICAL HIGHLIGHTS
CARDINAL SIGNS
Celsus in first century AD,first listed the four signs
-Rubor(redness)
-Tumor(swelling)
-Calor(heat) &
-Dolor(pain)
-a fifth clinical sign,loss of function(functio lasea) -
Rudolf virchow in seventeenth century.
These signs are typically more prominent in acute
inflammation than in chronic inflammation
9. ACUTE INFLAMMATION
It is a rapid new response to an injurious agent that
serves to deliver mediators of host response-
leukocytes and plasma proteins-to the site of injury.
It is of relatively short duration,lasting for
minutes,several hours or a few days .
10. COMPONENTS OF ACUTE INFLAMMATION
It has three major components:
1. Alterations in vascular caliber that lead to an increase
in blood flow
2. Structural changes in the microvasculature(increased
vascular permeability) that permit plasma proteins and
leukocytes to leave the circulation.
3. Emigration of the leukocytes from the
microcirculation,their accumulation in the focus of
injury,and their activation to eliminate the offending
agent.
11.
12. STIMULI FOR ACUTE INFLAMMATION
Infections(bacterial,viral,parasitic)and microbial
toxins
Trauma(blunt and penetrating)
Physical and chemical agents(thermal injury,e.g.,burns
or frostbite;irradiation;some environmental chemicals)
Tissue necrosis
Foreign bodies(splinters,dirt,sutures)
Immune reactions(called hypersensitivity reactions)
13. VASCULAR CHANGES
Changes in vascular flow and caliber begin very early
after injury and ,depends on the severity of injury.
They occur in the following order-
1. Vasodilation
2. Slowing of the circulation
3. Leukocytic margination
14. VASODILATATION
Following an inconstant and transient
vasoconstriction of arterioles,lasting a few
seconds,vasodilatation occurs.
This first involves the arterioles and then results in
opening of new capillary beds in the area.Thus
comes about the increased blood flow(cause of the
heat and the redness.)
It is induced by the action of mediators histamine
& nitric oxide on vascular smooth muscle.
15. SLOWING OF THE CIRCULATION
Vasodilatation is followed by increased permeability
of the microvasculature,with the outpouring of
protein rich fluid into the extravascular tissues.
The latter results in concentration of red cells in small
vessels and increased viscosity of blood,reflected by
the presence of dilated small vessels packed with red
cells & slower blood flow termed stasis.(rubor)
16. LEKOCYTIC MARGINATION
As stasis develops peripheral orientation of leukocytes
occur,pricipally neutrophils,along the vascular
endothelium,a process called leukocytic
margination.
Leukocytes then stick to the endothelium,at first
transiently(rolling),then more avidly and soon they
migrate into the interstitial tissue .
The time scale of these events is
variable.With mild stimuli the stages of stasis may not
become apparent until 15 to 20 minutes have
elapsed,whereas with severe injury ,stasis may occur
in a few minutes,
17. INCREASED VSCULAR PERMEABILITY
(vascular leakage)
Increased vascular permeability leading to the escape
of protein rich fluid into the interstitium is the
hallmark of acute inflammation.
The loss of protein rich fluid from the plasma reduces
the intravascular osmotic pressure and increases the
osmotic pressure of the interstitial fluid.
Together with the increased hydrostatic pressure due
to vasodilatation,this leads to a marked outflow of
fluid and its accumulation in the interstitial tissue.This
net increase of extravascular fluid is edema.
18. •Normal fluid exchange µvascular permeability
are dependent on an intact endothelium.
Endothelium becomes leaky in inflammation.
Five mechanisms are known.
20. 1.ENDOTHELIAL CONTRACTION
Endothelial cell contraction,leads to the formation of
widened intercellular junctions,or intercellular
gaps.This is the most common method of vascular
leakage.
It is elicited by histamine,bradykinin,leukotrienes
and other classes of chemical mediators.
It is usually reversible and short-lived,(15-30
minutes)& is thus known as the immediate transient
response.
This type of leakage mainly affects only venules
leaving capillaries and arterioles unaffected.
21. Binding of the mediators to their receptors on
endothelial cells activates intracellular signaling
pathways that lead to phosphorylation of contractile
and cytoskeleton proteins such as myosin.
These proteins contract ,leading to contraction of
endothelial cells & seperation of intercellular
junctions.
22. 2.CYTOSKELETAL AND JUNCTIONAL
REORGANIZATION(endothelial retraction)
A different mechanism of reversible intercellular
leakage,resulting in interendothelial gaps,can be
induced in vitro by cytokine mediators,such as –
interleukin-1(IL-1),
tumor necrosis factor(TNF),and
interferon-gamma(INF-ᵧ).
These cytokines increase the vascular permeability by
inducing a structural reorganization of the
cytoskeleton.
23. Such that the endothelial cells retract from one
another along their junctions, leading to the
interendothelial gaps.
Cytokine induced response is somewhat delayed (4-
6hrs) and long-lived(24hrs or more) in contrast to the
histamine effect.
24. 3.DIRECT ENDOTHELIAL INJURY
It results in endothelial cell necrosis and detachment.
This effect is usually encountered in necrotizing
injuries.
It is due to direct damage to the endothelium by the
injurious stimulus eg. Severe burns or lytic bacterial
infections.
Reaction is of TWO types-
Immediate sustained response
Delayed prolonged response
25. IMMEDIATE SUSTAINED RESPONSE
1. Mostly, leakage starts immediately after injury & is
sustained at higher level for several hours until the
damaged vessels are thrombosed or repaired.
2. All levels of the microcirculation are
effected.including venules,capillaries and arterioles.
26. DELAYED PROLONGED LEAKAGE
It is a common type of increased permeability that begins
after a delay of 2 to 12 hours,lasts for several hours or even
days.
It involves venules as well as capillaries.
Such leakage is caused by mild to moderate thermal
injury,X-or ultraviolet irradiation & certain bacterial toxins
-The late appearing sunburn is a good example of a
delayed reaction
It is attributable to apoptosis and the action of cytokines.
27. 4.LEUKOCYTE-DEPENDENT ENDOTHELIAL INJURY
may occur as a result of leukocyte accumulation during the
inflammatory response.
Leukocytes adhere to the endothelium & may be activated in
the process.
Releasing toxic oxygen species and proteolytic enzymes
Which then cause endothelial injury.
Largely restricted to venules and pulmonary capillaries
Late response
Long lived
28. 5.INCREASED TRANSCYTOSIS
Transcytosis occurs mainly through vesiculovacuolar
organelle accross the intercellular junctions.
venules
Induced by histamine & most chemical mediators
Certain factors eg.VEGF(vascular endothelial growth
factor) causes vascular leakage by increasing the no. &
size of these channels.
29. 6.Leakage from new blood vessels
New vessel sprouts remain leaky during angiogenesis
Certain factors eg.VEGF also increase vascular
permeability.
This causes edema which is the characteristic of early
phase of healing.
Although these mechanisms are
seperable,they may all participate in response to any
particular stimulus eg various stages of thermal burn
Different chemical mediators may be produced in
consecutive phases of the inflammatory response
resulting in delayed or sustained vascular changes.
31. EVENTS IN EXTRAVASATION OF LEUKOCYTES
Margination & rolling
Adhesion &transmigration across the
endothelium(DIAPEDESIS)
Migration in interstitial tissues toward a chemotactic
stimulus
32. Margination & rolling
In normal blood flow ,erythrocytes are confined to a
central axial column displacing the leukocytes towards the
wall of the vessel
As vascular permeability increases in early inflammation,
blood flow slows(stasis),hemodynamic conditions change
& more white cells assume a peripheral position along the
endothelial surface.
This process of leukocyte accumulation is called
MARGINATION
33. Subsequently,the leukocytes tumble slowly along the
endothelium &adhere transiently(rolling).
In time endothelium can be lined by white cells,an
appearance called PAVEMENTING.
ADHESIONS involved in rolling are accounted by
selectin family of molecules
34.
35. LEUKOCYTE ADHESION & TRANSMIGRATION
Eventually leukocytes firmly adhere to the endothelial
surface(adhesion) before crawling between the cells &
through the basement membrane into the extravascular
space(diapedesis)
It is regulated largely by the binding of complimentary
adhesion molecules on the leukocytes & endothelial
surfaces,& chemical mediators(chemoattractants & certain
cytokines) modulate the surface expression of adhesion
molecules.
36. The adhesion receptors involved belong to four
molecular families-
1. Selectins
2. The immunoglobulin family
3. Integrins
4. Mucin-like glycoproteins
37. SELECTINS
Characterized by N-terminal domain related to sugar-
binding mammalian lectins,consists of-
E-selectin(CD62E OR ELAM-1)
P-selectin(CD62P or GMP140 or PADGEM)
L-selectin(CD62L or LAM-1)
E & P selectins bind through their lectin domains to
sialyl-Lewis X oligosaccharide on certain
glycoprotein on leukocytes.
38. IMMUNOGLOBULIN FAMILY
IT INCLUDES-
2 endothelial adhesion molecules
1. ICAM-1(intercellular adhesion molecule)
2. VCAM-1(vascular cell adhesion molecule)
3. Both serve as ligands for integrins found on
leukocytes.
39. INTEGRINS
Are transmembrane heterodimeric glycoproteins,made
up of α and β chains.
Are expressed on many cell types & bind to ligands
on endothelial cells,other leukocytes & the
extracellular matrix.
Eg- β2 integrins LFA-1 & Mac-1 bind to ICAM-1
β1 integrins VLA-4 bind VCAM-1
40. MUCIN LIKE GLYCOPROTEINS
Such as haparan sulphate serve as ligand for the
leukocyte adhesion molecule called CD44.
These are found in the extracellular matrix and on cell
surfaces.
41. Initial adhesion(rolling) is through selectins &
glycosylated proteins.
E &P selectins are upregulated at the inflammatory sites
by specific mediators.
L selectins on leukocytes bind CD34 glycoproteins on
endothelial cells.
Activation of leukocytes by selectin binding & mediators
increases integrin avidity.
Firm adhesion occurs via integrin endothelial cell receptor
interaction.LFA-1 & Mac-1 integrins are on all leukocytes
& bind to ICAM-1 on endothelial cells.
Homotypic interaction of PECAM-1(CD31) on leukocytes
& endothelial cells mediates transmigration between
cells.(diapedesis).
42.
43. CHEMOTAXIS &ACTIVATION
After extravasation,leukocytes emigrate towards the site
of injury,along a chemical gradient in a process called
chemotaxis.
Both exogenous & endogenous substances can act as
chemotactic agents for leukocytes.
Most common exogenous agents are bacterial products
eg-peptides that possess N-formyl-methionine terminal
amino acid.
44. Endogenous chemoattractants include chemical mediators-
1. Components of the complement system,C5a
2. Products of the lipoxygenase pathway.leukotriene B4 &
3. cytokines(IL-8)
Chemotactic agents bind to the specific receptors on the
leukocyte cell surface & induce an intracellular cascade of
phospholipid metabolites leading to increased intracellular
calcium.
Increased cytosolic calcium triggers the assembly of
cytoskeketal contractile elements.
Leukocytes move by extending pseudopods.
The direction of movement is specified by a higher density of
receptor-ligand interactions on one side of the cell.
Locomotion involves assembling actin monomers into
crosslinked polymers at the pseudopod’s leading edge.
45. Leukocyte activation
Chemotactic factors also induce leukocyte activation
Leukocytic activation result in-
1. Production of AA metabolites.
2. Degranulation & secretion of lysosomal enzymes &
generation of oxidative bursts
3. Modulation of leukocyte adhesion molecules including
increased( or decreased) numbers & increased( or
decreased) affinities.
46. PHAGOCYTOSIS
Phagocytosis & release of lysosomal enzymes are the two
major benefits from the accumulation of leukocytes at the
site of inflammation.
It consists of three main steps-
1. Recognition & the attachment of the particle to the
ingesting leukocyte
2. Engulfment, with the subsequent formation of a
phagocytic vaculoe
3. Killing or degradation of the ingested material.
47. Recognition &attachment
Neutrophils & macrophages can engulf the bacteria by
recognition of the particles by the receptors expressed on
the leukocyte surface.
Mannose &scavenger receptors are the two important
receptors that function to bind & ingest microbes.
The efficiency of phagocytosis is greately enhanced when
microbes are coated with serum proteins called opsonins
(opsonization)for which the phagocytes express high
affinity receptors.eg-IgG antibodies(Fc portion),the C3b
breakdown product of complement (C3bi)& certain
plasma lectins-MBL,all of which are recognized by
specific receptors on leukocytes.
48. ENGULFMENT
Binding of the opsonized particles triggers engulfment.
Pseudopods are extended around the object to be
engulfed forming a phagocytic vaculoe.
The membrane of the vaculoe then fuses with the
membrane of the lysosomal granule .
Contents of the lysosomal granule are discharged into the
phagolysosome resulting in degranulation of the
leukocyte .
49. Killing & degradation
Bacterial & microbial killing is accomplished largely by
reactive oxygen species.
Phagocytosis stimulates oxydative bursts characterized by
a sudden increase in oxygen consumption,
glycogen catabolism(glycogenolysis)
Increase glucose oxidation,
Production of reactive oxygen metabolites.
Oxygen metabolites are generated due to rapid activation of a
leukocyte NADPH oxidase ,which oxidizes NADPH & in the
process reduces O2 to superoxide ion( O2
- )
51. Superoxide is then converted into hydrogen peroxide by
dismutation.
Lysosomes of neutrophils (azurophilic granules) contain the
enzyme myeloperoxidase (MPO) & in the presence of halide
such as Cl- ,MPO converts H2O2 to HOCl- which is a powerful
oxidant and antimicrobial agent that kills the bacteria by
halogenation,protein & lipid peroxidation.
Dead microorganisms are degraded by the action of lysosomal
acid hydrolases.
Other constituents of the leukocyte granules are capable of
killing bacteria.these include
lysosome,lactoferrin,bactericidal permeability increasing
protein(BPI) & defensins.
53. LEUCOCYTE- INDUCED TISSUE INJURY
Activated leucocytes
Reactive oxygen species and products of AA metabolism
Direct endothelial injury and and tissue damage.
Persistent activation of the leukocytes
underlies many diseases in humans.
Eg-Rheumatoid arthritis,chronic lung disease)
54. DEFECTS IN LEUCOCYTE FUNCTION
Cause-genetic
-acquired
Vulnerability to infections
Infections can be -recurrent &
- life threatening
55. Three types
1. Defects in adhesion
1. LAD-I(Leucocyte Adhesion deficiency I)
caused by defective synthesis of CD 18 subunit of
leucocyte integrins LFA-1 and Mac-1
56. 2. LAD -2 –caused by general defect of fucose metabolism
Absence of sialyl-Lewis X(oligosaccharide epitope
that binds E- and P- selectins)
57. 2. Defects in chemotaxis or phagocytosis
Chediak Higashi syndrome
caused by
Disordered assembly of microtubules
Results in
Impaired locomotion & lysosomal degranulation into
phagosomes
58. 3. Defects in microbicidal activity
Chronic granalumatous lung disease
Genetic deficiency in a component of
NADPH oxidase (generates superoxide)
Engulfment of bacteria doesn’t result in oxygen
dependent killing mechanism.
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