Innate Pattern Recognition Receptor and Acetaminophen-induced Liver Injury

对乙酰氨基酚(APAP)引起的肝毒性已成为急性肝功能衰竭的主要原因 在普通人群和退伍军人中。APAP过量或滥用导致严重肝损伤仍是一种 对退伍军人的巨大威胁。目前，实施的护理标准使用高剂量的L-半胱氨酸前体 N-乙酰半胱氨酸(NAC)使其成为APAP诱导的肝损伤患者的唯一治疗选择 (艾力)。不幸的是，在过量用药和治疗之间使用NAC的治疗窗口很窄。 使许多患者没有其他来源。病理性认识的研究重点 AILI的作用机制一直是肝细胞内的变化。然而，新出现的证据 提示无菌炎症在改变疾病进展的结果方面起着关键作用。我们的预赛 研究表明，消融清道夫受体A(SRA)主要是一种固有的模式识别受体 表达在髓系细胞上，如枯否细胞(KCs)，可加重AILI，表明死亡率急剧上升 和肝脏炎症。这与抗炎细胞因子的产生显著减少有关。 IL-10。APAP暴露后人体血液样本中SRA的表达与IL-10水平也呈正相关。 SRa-IL-10途径调节复杂的炎症级联反应，包括非常规γδT的激活 已知会加重组织损伤的细胞。我们的中心假设是SRA充当主调节器 改善肝脏免疫功能，促进肝脏动态平衡。这个项目的目标是审问和 从机制上理解SRA是一个关键的肝脏免疫“检查点”，在高度整合的免疫系统中运作 AILI期间的流程。这些包括KC对损伤相关分子模式的反应 肝细胞损伤、肝细胞内源性应激信号的调节和致病因子的动员 炎性细胞。还将对APAP过量患者的临床标本进行免疫变化分析 在动物模型中验证我们的发现。此外，我们将测试以SRA为目标的可行性- 调节免疫网络，提高AILI的NAC治疗水平。成功完成这项研究将 加深对AILI一种新的肝细胞外源性免疫机制的认识。预计 作为AILI以前未被认识的免疫决定因素，SRA的关键作用将被确立为第一个 时间到了。考虑到退伍军人服药过量或滥用的风险增加，我们的研究具有非常重要的意义 在临床上与退伍军人的医疗保健相关。阐明决定因素的关键要素和分子途径 AILI的发病机制不仅有助于识别危险因素，降低AILI的发生率，还将为AILI的发生提供 开发新的免疫靶向疗法的新机会，使大批退伍军人受益。

Hepatotoxicity induced by acetaminophen (APAP) has become the leading cause of acute liver failure among the general and the VA populations. The APAP overdose or abuse causing severe liver injury remains a great threat to veterans. Currently, the standard of care implemented uses high doses of the L-cysteine precursor N-Acetylcysteine (NAC) making it the only treatment option for patients that suffer from APAP-induced liver injury (AILI). Unfortunately, the therapeutic window of NAC administration between overdose and treatment is narrow leaving many patients with no other recourses. The focus of research in understanding the pathologic mechanisms of AILI has been always on intracellular changes in hepatocytes. However, emerging evidence suggests a critical role of sterile inflammation for modifying the outcome of disease progression. Our preliminary studies showed that ablation of scavenger receptor A (SRA), an innate pattern recognition receptor primarily expressed on myeloid cells, e.g., Kupffer cells (KCs), exacerbated AILI indicated by sharply increased mortality and hepatic inflammation. This was associated with markedly reduced production of anti-inflammatory cytokine IL-10. SRA expression also positively correlates with IL-10 levels in human blood samples after APAP exposure. SRA-IL-10 pathway regulates a sophisticated inflammatory cascade including activation of unconventional γδ T cells that are known to aggravate tissue damage. Our central hypothesis is that SRA acts as a master regulator of hepatic immunity and promotes liver homeostasis in AILI. The objective of this project is to interrogate and mechanistically understand SRA as a key hepatic immune `checkpoint' that operates in highly integrated immune processes during AILI. These include KC response to damage-associated molecular patterns released from injured hepatocytes, modulation of hepatocyte-intrinsic stress signaling, and mobilization of pathogenic inflammatory cells. Analyses of clinical specimens from APAP overdose patients for immune alterations will also be performed to validate our findings in animal models. Furthermore, we will test the feasibility of targeting SRA- regulated immune network to improve NAC treatment of AILI. Successful completion of this research will advance our understanding of a novel hepatocyte-extrinsic immunologic mechanism of AILI. It is anticipated that a crucial role of SRA, as a previously unrecognized immune determinant of AILI, will be established for the first time. Given an increased risk of drug overdose or abuse among veterans, our research is highly significant and clinically relevant to the healthcare of veterans. Elucidating the key elements and molecular pathways that define the pathogenesis of AILI not only will help identify risk factors to decrease the incidence of AILI, but also provide new opportunities to develop novel immune-targeted therapies that benefit the large population of veterans.