| First Author | Sparkenbaugh EM | Year | 2011 |
| Journal | J Pharmacol Exp Ther | Volume | 338 |
| Issue | 2 | Pages | 492-502 |
| PubMed ID | 21576378 | Mgi Jnum | J:196046 |
| Mgi Id | MGI:5486437 | Doi | 10.1124/jpet.111.180521 |
| Citation | Sparkenbaugh EM, et al. (2011) The role of hypoxia-inducible factor-1alpha in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 338(2):492-502 |
| abstractText | Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha in mouse livers and isolated hepatocytes downstream of oxidative stress. HIF-1alpha signaling controls many factors that contribute to APAP hepatotoxicity, including mitochondrial cell death, inflammation, and hemostasis. Therefore, we tested the hypothesis that HIF-1alpha contributes to APAP hepatotoxicity. Conditional HIF-1alpha deletion was generated in mice using an inducible Cre-lox system. Control (HIF-1alpha-sufficient) mice developed severe liver injury 6 and 24 h after APAP overdose (400 mg/kg). HIF-1alpha-deficient mice were protected from APAP hepatotoxicity at 6 h, but developed severe liver injury by 24 h, suggesting that HIF-1alpha is involved in the early stage of APAP toxicity. In further studies, HIF-1alpha-deficient mice had attenuated thrombin generation and reduced plasminogen activator inhibitor-1 production compared with control mice, indicating that HIF-1alpha signaling contributes to hemostasis in APAP hepatotoxicity. Finally, HIF-1alpha-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-1alpha contributes to hemostasis, sterile inflammation, and early hepatocellular necrosis during the pathogenesis of APAP toxicity. |
