Recently we observed the massive accumulation of polymorphonuclear neutrophils (PMN) in the liver during reperfusion after ischemia and also during acetaminophen (AAP)-induced injury. Preliminary data suggest that PMN may actively contribute to the tissue damage in these two models of hepatic injury. The chemotactic signal recruiting the PMN appears to be reactive oxygen in both models. The main objectives of this proposal therefore are to confirm that reactive oxygen is the signal, to identify the source(s) of the reactive oxygen, to confirm the direct relationship between PMN accumulation and tissue damage by various pharmacological interventions, and to quantify the metabolic and physiologic contributions to the liver injury of PMN accumulation itself versus the ischemic insult or the direct damage by AAP. In a model of hepatic ischemia and reperfusion the effect of selective pharmacological interventions on organ, cell, and mitochondrial injury will be studied in vivo and compared with the similar model in the isolated blood-free rat perfused liver. Drugs include oxyradical and radical scavengers, xanthine oxidase inhibitors, Kupffer cell inhibitors and simulators, iron and iron chelators (to study the involvement of lipid peroxidation) and lipoxygenase inhibitors (to study the involvement of eicosatetraenoic acid- derived mediators in the recruitment of PMN during reperfusion injury). The contribution of PMN in AAP-induced injury will be investigated in an in vivo model using similar pharmacological interventions as described above and compared quantitatively with the effects of these drugs on AAP-induced injury in the blood-free perfused mouse liver. Our hypothesis is that injury produced by the reactive metabolite of AAP leads to PMN accumulation, secondary alteration of the hepatic microvascular circulation, and an extension of the AAP injury by the PMN-mediated low blood flow ischemia. The studies should clarify the role of PMN in the pathophysiology of ischemia-reperfusion and AAP-induced hepatic injury and provide rationales for new therapeutic interventions in various liver diseases.
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