2. Inflammation is defined as the local response of
living mammalian tissues to injury due to any agent.
It is a body defense reaction in order to eliminate or
limit the spread of injurious agent, followed by
removal of the necrosed cells and tissues.
DEFINITION
3. Agents causing inflammation
1. Infective agents like bacteria, viruses and their
toxins, fungi, parasites.
2. Immunological agents like cell-mediated and
antigen antibody reactions.
3. Physical agents like heat, cold, radiation,
mechanical trauma.
4. Chemical agents like organic and inorganic
poisons.
5. Inert materials such as foreign bodies.
4. SIGNS OF INFLAMMATION
The Roman writer Celsus in 1st century A.D. named
the famous 4 cardinal signs of inflammation as:
rubor (redness);
tumor (swelling);
calor (heat);
dolor (pain).
fifth sign functio laesa (loss of function) was later
added by Virchow.
5. TYPES OF INFLAMMATION
Depending upon the defense capacity of the host
and duration of response, inflammation can be
classified as
acute
chronic
7. Vascular events
transient vasoconstriction
persistent progressive vasodilatation redness and
warmth
elevate the local hydrostatic pressure
transudation of fluid into the extracellular space
swelling
Slowing or stasis of microcirculation increased
concentration of red cells raised blood viscosity
leucocytic margination .
8.
9. Vasodilation
Brief arteriolar vasoconstriction followed by
vasodilation
Accounts for warmth and redness
Opens microvascular beds
Increased intravascular pressure causes an early
transudate (protein-poor filtrate of plasma) into
interstitium
10. Vascular leakage
Vascular permeability (leakiness) commences
Transudate gives way to exudate (protein-rich)
Increases interstitial osmotic pressure contributing to
edema
11. Vascular leakage
Five mechanisms known to cause vascular leakiness
Histamines, bradykinins, leukotrienes cause an early, brief (15 – 30
min.) immediate transient response in the form of endothelial cell
contraction that widens intercellular gaps of venules.
Cytokine mediators (TNF, IL-1) induce endothelial cell junction
retraction through cytoskeleton reorganization (4 – 6 hrs post
injury, lasting 24 hrs or more)
Severe injuries may cause immediate direct endothelial cell damage
(necrosis, detachment) making them leaky until they are repaired
(immediate sustained response), or may cause delayed damage as in
thermal or UV injury, or some bacterial toxins (delayed prolonged
leakage)
Marginating and endothelial cell-adherent leukocytes may pile-up
and damage the endothelium through activation and release of
toxic oxygen radicals and proteolytic enzymes (leukocyte-dependent
endothelial cell injury) making the vessel leaky
Certain mediators (VEGF) may cause increased transcytosis – in
neovascularisation
12. Leukocyte cellular events
Leukocytes leave the vasculature routinely
through the following sequence of events:
Margination and rolling
Adhesion and transmigration
Chemotaxis and activation
They are then free to participate in:
Phagocytosis and degranulation
Leukocyte-induced tissue injury
13.
14. Margination and Rolling
With increased vascular permeability, fluid leaves the
vessel causing leukocytes to settle-out of the central
flow column and “marginate” along the endothelial
surface
Endothelial cells and leukocytes have complementary
surface adhesion molecules which briefly stick and
release causing the leukocyte to roll along the
endothelium like a tumbleweed until it eventually
comes to a stop as mutual adhesion reaches a peak.
15. Margination and Rolling
Early rolling adhesion mediated by selectin family:
E-selectin (endothelium),
P-selectin (platelets, endothelium),
L-selectin (leukocytes)
bind other surface molecules (i.e.,CD34, Sialyl-Lewis
X-modified GP) that are upregulated on endothelium
by cytokines (TNF, IL-1) at injury sites
16. Adhesion
Rolling comes to a stop and adhesion results
Other sets of adhesion molecules participate:
Endothelial: ICAM-1, VCAM-1
Leukocyte: LFA-1, Mac-1, VLA-4
(Intercellular Adhesion Molecule-ICAM, vascular cell adhesion molecule -VCAM, Lymphocyte function-
associated antigen -LFA, very late activation antigen 1-VLA)
17. Transmigration (diapedesis)
Occurs after firm adhesion within the systemic
venules and pulmonary capillaries via PECAM –1
(CD31)
Must then cross basement membrane
Collagenases
Integrins
Platelet endothelial cell adhesion molecule (PECAM-1)
18. Chemotaxis
Leukocytes follow chemical gradient to site of
injury (chemotaxis)
Soluble bacterial products
Complement components (C5a)
Cytokines (chemokine family e.g., IL-8)
Leukocytes:
extend pseudopods with overlying surface adhesion
molecules (integrins) that bind ECM during
chemotaxis
19.
20. Phagocytosis and Degranulation
Once at site of injury, leukocytes:
Recognize and attach
Engulf (form phagocytic vacuole)
Kill (degrade)
21. Recognition and Binding
Opsonized by serum complement, immunoglobulin (C3b,
Fc portion of IgG)
Corresponding receptors on leukocytes (FcR, CR1, 2, 3)
leads to binding
22. Phagocytosis and Degranulation
Triggers an oxidative burst ; engulfment and formation of
vacuole which fuses with lysosomal granule membrane
(phagolysosome)
Granules discharge within phagolysosome and
extracellularly (degranulation)
23. Disposal of microorganisms can proceed by following
mechanisms:
A. Intracellular mechanisms:
i) Oxidative bactericidal mechanism by oxygen free
radicals
a) MPO-dependent
b) MPO-independent
ii) Oxidative bactericidal mechanism by lysosomal
granules
iii) Non-oxidative bactericidal mechanism
B. Extracellular mechanisms:
24. Oxidative bactericidal mechanism by oxygen free radicals
MPO-dependent killing : In this mechanism, the enzyme
MPO acts on H2O2 in the presence of halides (chloride,
iodide or bromide) to form hypohalous acid (HOCl, HOI,
HOBr). This is called H2O2-MPO-halide system and is
more potent antibacterial system in polymorphs than
H2O2 alone.
25. MPO-independent killing : Mature macrophages lack the
enzyme MPO and they 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):
26. Leukocyte granules
Other antimicrobials in leukocyte granules:
Bactericidal permeability increasing protein (BPI)
Lysozyme
Lactoferrin
Defensins (punch holes in membranes)
27.
28.
29. Chemical mediators
I. CELL-DERIVED MEDIATORS
1. Vasoactive amines (Histamine, 5-hydroxytryptamine, neuropeptides)
2. Arachidonic acid metabolites (Eicosanoids)
i. Metabolites via cyclo-oxygenase pathway (prostaglandins, thromboxane
A2, prostacyclin, resolvins)
ii. Metabolites via lipo-oxygenase pathway (5-HETE, leukotrienes, lipoxins)
3. Lysosomal components (from PMNs, macrophages)
4. Platelet activating factor
5. Cytokines (IL-1, TNF-α, TNF-β, IFN-γ, chemokines)
6. Free radicals (Oxygen metabolites, nitric oxide)
II. PLASMA-DERIVED MEDIATORS (PLASMA PROTEASES) Products of:
1. The kinin system
2. The clotting system
3. The fibrinolytic system
4. The complement system
37. Possible outcomes of acute inflammation
Complete resolution
Little tissue damage
Capable of regeneration & restoration of injury cell to normal
Resolution involves – neutralization, spontaneous decay of
chemical mediators ,subsequent return of normal vascular
permeability ,cessation of leukocyte infiltration ,death by apoptosis
removes edema ,protein, foreign substance & necrotic debris .
Scarring (fibrosis)
In tissues unable to regenerate
Excessive fibrin deposition organized into fibrous tissue
in many pyogenic infection – intense neutrophil infiltration
&liquefaction of tissue – pus formation- fibrosis.
Abscess formation occurs with some bacterial or fungal
infections
Pneumonia, chronic lung abscess, peptic ulcer of duodenum or
stomach –persist months or yrs
Progression to chronic inflammation
39. Chronic inflammation is defined as prolonged
process in which tissue destruction and
inflammation occur at the same time.
1. Chronic inflammation following acute inflammation
2. Recurrent attacks of acute inflammation
3. Chronic inflammation starting de novo
40. GENERAL FEATURES OF
CHRONIC INFLAMMATION
1. MONONUCLEAR CELL INFILTRATION.
phagocytes
lymphoid cells.
Phagocytes -- circulating monocytes, tissue macrophages,
epithelioid cells and sometimes, multinucleated giant cells.
The macrophages comprise the most important cells in chronic
inflammation.
On activation, macrophages release several biologically active
substances e.g. acid and neutral proteases, oxygen-derived
reactive metabolites and cytokines. These products bring about
tissue destruction, neovascularisation and fibrosis.
Other chronic inflammatory cells -- lymphocytes, plasma cells,
eosinophils and mast cells.
41. 2. TISSUE DESTRUCTION OR NECROSIS.
brought about by activated macrophages which release a
variety of biologically active substances e.g. protease,
elastase, collagenase, lipase, reactive oxygen radicals,
cytokines (IL-1, IL-8, TNF-α), nitric oxide, angiogenesis
growth factor etc.
3. PROLIFERATIVE CHANGES.
As a result of necrosis, proliferation of small blood
vessels and fibroblasts is stimulated resulting in
formation of inflammatory granulation tissue.
Eventually, healing by fibrosis and collagen laying takes
place.
42. TYPES OF CHRONIC
INFLAMMATION
1. Non-specific, when the irritant substance produces
a nonspecific chronic inflammatory reaction with
formation of granulation tissue and healing by
fibrosis e.g. chronic osteomyelitis, chronic ulcer.
2. Specific, when the injurious agent causes a
characteristic histologic tissue response e.g.
tuberculosis, leprosy, syphilis.
43. 1. Chronic non-specific inflammation. It is
characterised by non-specific inflammatory cell
infiltration e.g. chronic osteomyelitis, lung abscess.
2. Chronic granulomatous inflammation. It is
characterised by formation of granulomas e.g.
tuberculosis, leprosy, syphilis, actinomycosis,
sarcoidosis etc.
44. GRANULOMATOUS INFLAMMATION
Granuloma is defined as a
circumscribed, tiny lesion, about 1
mm in diameter, composed
predominantly of collection of
modified macrophages called
epithelioid cells, and rimmed at
the periphery by lymphoid cells.
The word ‘granuloma’ is derived
from granule meaning
circumscribed granule-like lesion,
and -oma which is a suffix
commonly used for true tumours
but here it indicates a localised
inflammatory mass or collection
of macrophages