Acetaminophen (APAP) is the major cause of acute liver failure (ALF) in the U.S. The antidote, N- acetylcysteine (NAC), increases hepatic GSH, decreases covalent binding and is highly effective in the early stages of toxicity. However, after the onset of toxicity, NAC has limited efficacy and there is a high incidence of liver transplant or death in these patients. This proposal will investigate mechanisms of repair of APAP-induced toxicity because novel therapies are possible with augmentation of innate repair mechanisms in ALF secondary to APAP. Our preliminary studies reveal mechanisms of hepatocyte regeneration that are critical to recovery in the late stages of APAP mediated ALF. Oxidative stress, hypoxia inducible factor 1 alpha (HIF-1?) and vascular endothelial growth factor (VEGF) appear to play central roles in the liver's response to APAP toxicity. We show that HIF-1? and VEGF are dramatically increased in the livers of APAP intoxicated mice. Also, treatment with a VEGF inhibitor markedly delays hepatocyte regeneration. It is well established, in other model systems, that HIF-1? can regulate the levels of VEGF, however this has not been previously investigated in the liver. VEGF is an angiogenic factor important in organ repair. Although hypoxia is a well described mechanism of HIF-1? induction in many models, our recent data indicate that oxidative stress induces HIF-1? and is central to APAP mediated ALF. We have shown that HIF-1? is induced in freshly isolated mouse hepatocytes treated with APAP under normoxic conditions and blocked by inhibitors of oxidative stress. Using freshly isolated hepatocytes, we recently reported that APAP induced oxidative stress and mitochondrial permeability transition leading to cellular necrosis. We will test the three following hypotheses: 1) Oxidative stress leads to HIF-1? induction in APAP-mediated hepatotoxicity in mice. 2) Nuclear factor HIF-1? is critical for upregulation of VEGF synthesis in APAP toxicity in mice. 3) The interactions of VEGF and its receptors are critical to hepatocyte regeneration following APAP toxicity in mice. Lay description: This project will examine mechanisms of repair in the liver following acetaminophen toxicity in mice treated with acetaminophen. A better understanding of the recovery processes of the liver will lead to the development of new treatments for acute liver failure.
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