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Ischemia Reperfusion Injury

Ischemia Reperfusion Injury

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Ischemia Reperfusion Injury

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  1. Ischemia Reperfusion Injury Heider SH. AL-Qassam MSc.PH. &TH.

  2. I/ R Injury Ischemia (inadequate oxygen supply) local injury & impairment of organ function inflammatory responses Reperfusion

  3. Conditions under which I/R injury is encountered include • stroke • MI • organ transplantation • cardiopulmonary bypass

  4. Molecular and Cellular Basis of I/R Injury Molecular effects ATP depletion • Defective ATP-resynthesis • Increase in hypoxanthine • Activation of xanthine oxidase

  5. Generation of (ROS) (O2–, H2O2, OH-, ONOO–) Antioxidant (glutathione) depletion • Intracellular Na+ and Ca++-overload • Activation of NHE • Activation of PLA2 • Activation of NFkβ

  6. Cellular effects • Endothelial cell dysfunction/swelling • Leukocyte (PMN) recruitment • Impaired vasodilatation (NO-mediated) • Enhanced vasoconstriction(endothelin-mediated) • Endothelial barrier disruption • Expression of adhesion molecules

  7. Subcellular effects • Mitochondrial dysfunction/swelling • Translocation of bax • Efflux of cytochrome c • Lipid peroxidation • Cell membrane damage • Increased cell membrane permeability • Cytoskeletal derangements

  8. Mediators • Arachidonic acid metabolites (LTB4, TXA2) • Cytokines (IL-1b, IL-6, TNF-a) • Chemokines (IL-8, MCP-1) • Activated complement (C3a, C5a, C5b-9)

  9. Therapeutic Interventions Targeting I/R Injury • Anti-inflammatory • Inhibition of leukocyte accumulation • Complement inhibition (pexelizumab) • Inhibition of mPTP ( ex: cyclosporine) • Prevention of intracellular calcium overload • Reducing ROS by Inhibition of xanthine oxidase

  10. Thank you