PT - JOURNAL ARTICLE AU - Erica M. Sparkenbaugh AU - Yogesh Saini AU - Krista K. Greenwood AU - John J. LaPres AU - James P. Luyendyk AU - Bryan L. Copple AU - Jane F. Maddox AU - Patricia E. Ganey AU - Robert A. Roth TI - The Role of Hypoxia-Inducible Factor-1α in Acetaminophen Hepatotoxicity AID - 10.1124/jpet.111.180521 DP - 2011 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 492--502 VI - 338 IP - 2 4099 - http://jpet.aspetjournals.org/content/338/2/492.short 4100 - http://jpet.aspetjournals.org/content/338/2/492.full SO - J Pharmacol Exp Ther2011 Aug 01; 338 AB - Hypoxia-inducible factor-1α (HIF-1α) 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 (APAP) overdose, which is the leading cause of acute liver failure in the United States. APAP overdose has been reported to activate HIF-1α in mouse livers and isolated hepatocytes downstream of oxidative stress. HIF-1α signaling controls many factors that contribute to APAP hepatotoxicity, including mitochondrial cell death, inflammation, and hemostasis. Therefore, we tested the hypothesis that HIF-1α contributes to APAP hepatotoxicity. Conditional HIF-1α deletion was generated in mice using an inducible Cre-lox system. Control (HIF-1α-sufficient) mice developed severe liver injury 6 and 24 h after APAP overdose (400 mg/kg). HIF-1α-deficient mice were protected from APAP hepatotoxicity at 6 h, but developed severe liver injury by 24 h, suggesting that HIF-1α is involved in the early stage of APAP toxicity. In further studies, HIF-1α-deficient mice had attenuated thrombin generation and reduced plasminogen activator inhibitor-1 production compared with control mice, indicating that HIF-1α signaling contributes to hemostasis in APAP hepatotoxicity. Finally, HIF-1α-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-1α contributes to hemostasis, sterile inflammation, and early hepatocellular necrosis during the pathogenesis of APAP toxicity.