1. Dr. Ahmad Hameed MBBS,DCP, M.Phil
Inflammation
Dr. Ahmad Hameed
MBBS,DCP, M.Phil

2. Cytokines
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)

3. TNF & IL-1 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

4. Systemic Effects Fever Lethargy Increased sleep Decreased appetite
Hepatic synthesis of acute phase proteins
Metabolic wasting
Corticosteroids Synthesis
Neutrophil release in circulation
Fall in blood pressure

5. The roles of cytokines in acute inflammation
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.

6. Chemokines 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.
Receptors: CXCR4, CCR5

7. Chemokines CXC CC 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
Adjacent cysteine residues
MCP-1, MIP-1α
RANTES
Eotaxin

8. ROS 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 anti-proteases
Protective mechanisms( Catalase, Superoxide dismutase & Glutathione)

9. NO 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

10. Lysosomal Enzymes of WBCs
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

11. Destructive Effects of Lysosomal Enzymes
Proteases are checked by Anti-proteases e.g α1-antitrypsin is inhibitor of neutrophil elastase and α2 – macrogloblin
α1-antitrypsin deficiency in the lungs cause severe panacinar emphysema

12. Neuropeptides ( e.g Substance P)
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