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_Dr. Simon's lecture_pmi285

_Dr. Simon's lecture_pmi285 - Scott I Simon PMI285...

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    Neutrophil Recrutiment & Endothelial Transmigration Scott I. Simon PMI285 February 12, 2004 Biomedical Engineering
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    Inflammation Overview Neutrophils and the Innate response to Insult Signaling of Neutrophil Activation Adhesive and Chemokine receptors on Neutrophils  Multistep pattern of leukocyte recruitment Selectin Family of Adhesion Molecules Integrin Family of Adhesion Molecules Immunoglobulin Family of Adhesion Molecules Chemokines and Cytokines associated with Leukocyte recruitment Assembly of the inflammatory synapse between a PMN and inflamed      Endothelium    Regulation of Receptor  events during chemotaxis and TEM Mechanisms of Integrin Activation Neutrophil transendothelial migration
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    Innate immunity Refers to the basic resistance to disease that a species possesses - the first line of defense against infection . Characteristics of the innate immune response include: > Broad-Spectrum Responses not necessarily “bug” specific > There is no memory or lasting protective immunity > There is a limited repertoire of recognition molecules > The responses are phylogenetically ancient Potential pathogens are encountered routinely, but only rarely cause disease. The vast majority of microorganisms are destroyed within minutes or hours by innate defenses . Acquired specific immune response comes into play only if these innate defenses are breached.  i.e. Th1 and Th2  responses 
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    Leukocyte margination, transmigration and chemotaxis to the site of injury or infection. Multistep pattern of leukocyte recruitment Inflammation Is a defensive reaction of the innate immune system caused by infection, toxin exposure, or cell injury The inflammatory response involves three major stages: Rubor/Calor Dilation of arterioles, an increase in blood flow to capillaries and venules. Transcription of CAMs Increase in microvascular permeability resulting in escape of plasma proteins from the bloodstream. Alteration of gene expression & EC phenotype
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    Neutrophils Polymorphonuclear Leukocytes Most Common Leukocyte: 5 x 10 6 /mL blood t 1/2  ~ 6 hrs Segmented nucleus and granules Excess plasma membrane-microvilli Stimulatory Receptors: Chemotactic Receptors fMLP – bacterial product IL-8 – CXC chemokine PAF – phospholipid  LTB 4  – arachidonic acid  TNF- α  - cytokine  Complement Receptors  FcRII and FcRIII Adhesion Receptors:  Selectins (capture and rolling) Integrins (cell arrest and motility) Associated receptors (i.e. CD47)
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    Neutrophil Active Chemokines Mouse vs Man Human: CXCR1 binds IL-8 (CXCL8), GCP-2 (CXCL6) CXCR2 binds Gro- α/β/γ (CXCL1-3), ENA-78 (CXCL5), NAP-2 (CXCL7) CCR1 binds MIP-1 α (CCL3), MCP-3 (CCL7), HCC-1/2 (CCL14/15) Mouse: CXCR2 binds MIP-2 (hGro- α ), mKC, hIL-8, GCP-2 (hENA-78) CCR1 binds MIP-1 α
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