Inflammation The process of inflammation initiates from tissue injury or from foreign presence its initiation is triggered by the production of: a) chemokine (chemotactic) mediators….1 st siren! b) kinin sytem c) clotting system d) fibrinolytic system e) complement proteins Cytokines also play a “redundant” role in stim. inflammation From plasma

Role of chemokines (most important of the inflam mediators) Chemokines are cytokines which 1) mediate chemotaxis 2) stimulate adhesion of cells to endothelia 3) activate cells to respond to Ag More than 50 chemokines and at least 15 receptors have been reported

Inflammatory Chemokines Secreted by tissue cells in response to infection/injury. They cause: a) stimulation of adherence to endothelia by leukocytes (trigger formation of cell receptors) b) chemoattract leukocytes to site of infection Binding of chemokines to receptors initiates signal transduction of a variety of cell messengers causing: a) changes in leukocyte shape b) regulation of adhesins c) stimulate O2 dependent killing and proteases in phagocytes d) stimulate release of granules from granulocytes e) histamines from basophils

Some important chemokines: To name a few… IL-8 – Interleukin-8 GCP-2- Granulocyte chemotactic protein MCP-1,2,3,4- Monocyte chemoattractant protein MIP-1 – Macrophage inflammatory protein When they are released and contact either leukocytes or vasc endothelia -> they initiate signal transductions Chemokine receptors coupled with production of different chemokines by tissues regulates activities of leukocytes

Plasma enzyme mediators of Inflammation

Role of membrane phospholipids in inflammation P-lipids can be degraded to form: a) arachidonic acid and b) platelet activating factor (PAF)

Re: Cytokines play a co- stimulatory (redundant) role in triggering inflammation IL-1, IL-6, TNF-α  stimulate hypothalamus -> prostaglandin -> fever also  stimulate liver to produce “acute phase proteins TNF-α also has effects upon vasc.endothelia  > receptors and MØ  triggers secretion of CSF -> stimulates hematopoiesis IL-12  induces differentiation of T H 1 subset  induces release of IFN-γ by T and NK cells

The Inflammatory Process I physiological response to infection/injury Acute response – rapid onset/short duration w/i minutes – vasodilation >volume of blood, flow vascular permeability -> edema plasma contains 4 inflam mediators: kinins, clotting factors, fibrinolytic system, and complement Role of neutrophils – predom cell type early in response; peaks in tissue w/i first 6 hrs. By this time chemokines have stim levels of E + P selectins (thrombin and histamine trigger P; IL-1 and TNF-α trigger E) Chemokines stim production of mucin receptors on Neut’s IL-8 signal causes change in integrin for adhesion

The Inflammatory Process II After neutrophils extravasate, they release MIP-1 -MIP-1 attracts/activates MØ w/i 5 hrs MØ exhibit > phagocytosis; >cytokine release MØ cytokines induce local/systemic changes (IL-1, IL-6, TNF-α) cytokines also induce adherence and migration of Lymphocytes through endothelium

Localized Acute Inflammatory response

Systemic response to inflammation

Role of IFN-γ in Chronic Inflammation