The Role of Hypoxia-Inducible Factor-1 alpha in Acetaminophen Hepatotoxicity

[摘要]：Hypoxia-inducible factor-1 alpha 9HIF-1 alpha) is a critical transcription factor that controls oxygen homeostasis in response to hypoxia, inflammation, and oxidative stress. HIF has been implicated in the pathogenesis of liver injury in which these events play a role, including acetaminophen 9APAP) overdose, which is the leading cause of acute liver failure in the United States. APAP overdose has been reported to activate HIF-1 alpha in mouse livers and isolated hepatocytes downstream of oxidative stress. HIF-1 alpha signaling controls many factors that contribute to APAP hepatotoxicity, including mitochondrial cell death, inflammation, and hemostasis. Therefore, we tested the hypothesis that HIF-1 alpha contributes to APAP hepatotoxicity. Conditional HIF-1 alpha deletion was generated in mice using an inducible Cre-lox system. Control 9HIF-1 alpha-sufficient) mice developed severe liver injury 6 and 24 h after APAP overdose 9400 mg/kg). HIF-1 alpha-deficient mice were protected from APAP hepatotoxicity at 6 h, but developed severe liver injury by 24 h, suggesting that HIF-1 alpha is involved in the early stage of APAP toxicity. In further studies, HIF-1 alpha-deficient mice had attenuated thrombin generation and reduced plasminogen activator inhibitor-1 production compared with control mice, indicating that HIF-1 alpha signaling contributes to hemostasis in APAP hepatotoxicity. Finally, HIF1 alpha-deficient animals had decreased hepatic neutrophil accumulation and plasma concentrations of interleukin-6, keratinocyte chemoattractant, and regulated upon activation normal T cell expressed and secreted compared with control mice, suggesting an altered inflammatory response. HIF-1 alpha contributes to hemostasis, sterile inflammation, and early hepatocellular necrosis during the pathogenesis of APAP toxicity.

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