Overdose acetaminophen (APAP)-induced liver injury (AILI) accounts for nearly 50% of the acute liver failure cases each year. N-acetylcysteine (NAC) is the only antidote used clinically to ameliorate AILI; however, the effectiveness of NAC declines rapidly after APAP ingestion. Developing new life-saving treatment is critically needed. APAP-induced hepatocyte stress/damage results in the activation of liver resident M?s (Kupffer cells, KCs) and the recruitment of infiltrating M?s (IMs). We and others have demonstrated a hepato-protective function of hepatic M?s. A major goal of our research is to understand the underlying molecular mechanisms. APAP challenge causes profound liver tissue hypoxia, which triggers the stabilization of hypoxia-inducible factor (HIF)1? and HIF2?. Our preliminary studies using mice with myeloid-specific deletion of HIF2? (HIF2?mye/-) revealed a critical hepato-protective function of hepatic M?-derived HIF2?. Screening of the hepatic protective and pro-toxicant factors shows that IL-6 mRNA level is significantly lower in the liver and nonparenchymal cells of HIF2?mye/- mice compared with WT mice. It is recently reported that HIF2? directly regulates IL-6 transcription. Together, these findings led to our hypothesis that APAP treatment leads to HIF2? stabilization in hepatic M?s, and that HIF2?, via promoting IL-6 production, plays a critical role in M?-mediated hepato-protection. We propose three Specific Aims to examine this hypothesis:
(Aim 1). Determine the hepato-protective effect of the myeloid-specific HIF2?/IL-6 axis in AILI.
(Aim 2). Evaluate the therapeutic potential of HIF stabilization in attenuating AILI.
(Aim 3). Define the molecular mechanisms of the hepato-protective effects of myeloid-specific HIF2?/IL-6 axis. The findings will provide important insight into endogenous protective mechanisms during AILI. The knowledge gained could uncover therapeutic target and advance the development of antidote to treat patients with AILI.
/RELEVANCE Overdose acetaminophen (APAP)-induced liver injury (AILI) is the predominant cause of acute liver failure in the United States. The current treatment option for AILI is limited to N-acetylcysteine (NAC), which has a narrow therapeutic time window, resulting in the loss of a significant proportion of patients. The long-term goal of this research project is to better understand the molecular mechanisms involved in AILI in order to identify new therapeutic agents that will complement NAC in the treatment of AILI. Previous work has demonstrated a hepato-protective function of hepatic M?s in AILI. Our recent data suggest that hypoxia-inducible factor (HIF)2? may be important in mediating this protection. Successful completion of the proposed studies will not only provide insight into endogenous protective mechanisms during AILI, but also identify a potential therapeutic target. HIF can be pharmacologically activated by prolyl hydroxylase domain (PHD) inhibitors, which are currently used in clinical trials for the treatment of anemia and prevention of ischemia and reperfusion injury. Thus, HIF activation by PHD inhibitors could be swiftly translated into clinical studies in AILI patients.
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