Inflammation
Dr. Ahmad Hameed
MBBS,DCP, M.Phil
Cytokines
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Polypetide products of many cell types that
function as mediators of inflammation and
immunity
Some stimulate bone marrow precursors to
produce more WBCs
Some mediate communication between
WBCs(Interleukins)
Major cytokines in acute inflammation(TNF,
IL-1) and chronic inflammation (IFN-γ ,IL-12)
TNF & IL-1
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Produced by macrophages, mast cells, endothelial
cells
Stimulated by microbial products, immune
complexes, products of T-lymphocytes
 Endothelial effects
 Endothelial activation
expression of
adhesion molecules
 WBC binding & recruitment
 Procoagulant activity by TNF
 Increase in IL-1,IL-6,IL-8,PDGF, eicosanoids
 Fibroblast effects
 Activates tissue fibroblasts
 Increases proliferation, production of collagen
&ECM
Systemic Effects
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Fever
Lethargy
Increased sleep
Decreased appetite
Hepatic synthesis of acute phase proteins
Metabolic wasting
Corticosteroids Synthesis
Neutrophil release in circulation
Fall in blood pressure
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The roles of cytokines in acute inflammation. The cytokines TNF, IL-1, and
IL-6 are key mediators of leukocyte recruitment in local
inflammatory responses and also play important roles in the systemic
reactions of inflammation.
Chemokines
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Family of small 8-10 kDa proteins
Helps in recruitment and activation of
Leukocytes
Responsible for anatomic distribution of B
& T lymphocytes in different areas of lymph
nodes & spleen
Mediate their activities by binding to
specific G-protein coupled receptors on
target cells.
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Receptors: CXCR4, CCR5
Chemokines
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CXC
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One amino acid separating the cysteines
Act primarily on neutrophil
IL-8
 Produced by macrophages, endothelial cells, mast
cells, fibroblasts
 Produced in response to microbial products, IL-1 and
TNF
CC
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Adjacent cysteine residues
MCP-1, MIP-1α
RANTES
Eotaxin
ROS
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Produced by NADPH oxidase in neutrophils &
macrophages
Activated by microbes, immune complexes, cytokines
With in lysosome destroy phagocytosed microbes and
nectrotic cells
At low levels, increases cytokines & adhesion molecule
expression ,destroy phagocytosed microbes & necrotic
tissues
At high levels, cause tissue injury by endothelial
damage, breakdown of ECM because of protease
activation and an
Direct injury to other cell types ,inactivation of antiproteases
Protective mechanisms( Catalase, Superoxide
dismutase & Glutathione)
NO
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Short lived, soluble, free radical gas
Produced by neurons, macrophages & endothelial cells
nNOS, iNOS (IL-1, TNF, IFN-γ, bacterial endotoxins) also
present hepatocytes, cardiac myocytes, resp epithelial cells,
eNOS
Functions
 Cytotoxic to microbes(Microbicidal)
 Vasodialation
 ↑ Increase vascular permeability
 Inhibits platelet adhesion,aggregation & degranulation
 Inhibits WBC adhesion & recruitment
 ↓ Decrease cellular response
Lysosomal Enzymes of WBCs
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Capable of phagocytosis and tissue damage
Acid proteases
 Active only within phagolysosomes
Neutral proteases
 E.g. Elastase,Collagenase,Cathepsin
 Active in ECM, degrade elastin, collagen & other
matrix proteins
 Convert C3 & C5 to C3a & C5a
 Can convert HMWK to Bradykinin
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Destructive Effects of Lysosomal Enzymes
Proteases are checked by Anti-proteases e.g α1antitrypsin is inhibitor of neutrophil elastase and α2 –
macrogloblin
α1-antitrypsin deficiency in the lungs cause severe
panacinar emphysema
Neuropeptides ( e.g Substance P)
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Initiates inflammation
Transmit pain signals
Regulate vessel tone & thus vascular
permeability
Secreted by sensory nerves (lungs, GIT)
and leukocytes.
Stimulation of secretion by endocrine
cells
Regulate blood pressure