Inflammation In Ischemic Damage And Ischemic Tolerance

The brain's inflammatory response to ischemia exacerbates ischemic brain damage (77,78). Expression of proinflammatory cytokines, such as tumor necrosis factor a (TNF-a) and inter-leukin 1 (IL-1), is increased after cerebral ischemia (79), and inhibition of cytokine expression reduces ischemic damage (80). Both cytokines, however, have also been implicated in tolerance induction. Serum IL-1 increases after global ischemic preconditioning in gerbils, and administration of antibody against its receptor blocks tolerance induction (81). Similarly, TNF-a expression in brain is increased after focal ischemic preconditioning in rats, which can be prevented with a neutralizing antibody against TNF-a (82). TNF-a also contributes to in vitro tolerance induction by hypoxic preconditioning (83). Because the production of pro-inflammatory cytokines in brain is probably initiated by signaling through Toll-like receptors (TLRs) that recognize molecules released from ischemia-injured brain tissues, it has been suggested that early preconditioning might be mediated via direct interference with membrane fluidity, disrupting lipid rafts and thereby inhibiting TLR/cytokine signaling pathways (84). Delayed preconditioning, on the other hand, triggers the TLR/cytokine inflammatory pathways, which leads to inflammation and, more importantly, to simultaneous upregulation of feedback inhibitors of inflammation. Activation of the transcription factor NF-kB appears to be a crucial step toward tolerance in these models (85,86). Cyclooxygenase-2 (COX-2), although widely implicated in tolerance induction in the heart (87,88), has not been shown to be relevant to preconditioning in brain.

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