Diverging roles of EGFR and MET in acetaminophen-induced acute liver injury

扑热息痛(APAP)过量是美国急性肝功能衰竭(ALF)的最主要原因，N- 乙酰半胱氨酸(NAC)是唯一可用的药物治疗方法。NAC仅在早期呈现时有效 患者，但这些患者中的大多数都是晚就医。因此，有一种未得到满足的临床需求 探索针对ALF后期阶段的替代药理学方法，如通过抑制进展 或通过促进代偿性肝再生。生长因子受体MET和EGFR是 被认为对肝部分切除(PH)后的肝再生是必要的，但它们在临床上的作用 APAP诱导的肝损伤(AILI)的相关模型尚不清楚。与PH不同的是，严重的肝脏损伤和 AILI过程中的炎症在很大程度上决定了其病理生理学，我们先前的研究表明， AILI模型中的这些生长因子受体不能被推定为与已知的在AILI模型的再生中相同 PH后的健康肝脏。事实上，我们之前发表的研究表明，早期EGFR具有意想不到的作用 激活在加重ALI中的作用，与其在肝细胞增殖中的传统作用相反 再生。我们发现，EGFR的激活与损伤的严重程度和使用EGFR的治疗有关 抑制剂(Canertinib)几乎完全消除小鼠的AILI。与EGFR相反，我们的初步研究 提示MET除发挥作用外，还参与积极抑制AILI时肝损伤的进展。 促进肝脏再生。因此，我们的首要假设是EGFR和MET起着截然相反的作用。 在APAP过量后的急性肝损伤中的相反作用，而不是传统上已知的和 在肝细胞增殖中功能相似的作用。与它们在肝脏再生中的相似作用相反， 在AILI模型中，MET直接抑制，矛盾的是，EGFR加重了急性肝损伤。建立 我们最初的发现提出的范式转变，我们的具体目标1和2将全面调查 EGFR和MET分别在APAP过量后肝损伤和代偿性再生中的作用 利用肝细胞特异性基因敲除和受体激活策略。此外，我们将调查 生长因子受体在AILI中的这些新作用的机制。就治疗相关性而言， 临床批准的EGFR抑制剂(Afatinib)和针对MET的干预措施的效果将被调查 AILI，尤其是在NAC无效的情况下，专注于临床相关的晚期干预。最后，对于人类来说 因此，我们还将调查我们的干预措施的效果，并验证井下的机制。 描述了艾力原代人肝细胞模型。这些研究不仅将阐明再生的作用 这是首次在具有临床意义的ALF模型中使用MET和EGFR，但也将揭示 与急性肝损伤相关的生长因子受体生物学的新方面。此外，成功完成了 这些研究将有助于确定临床上可用的EGFR抑制剂的再利用潜力。 和/或针对MET的干预措施来治疗APAP诱导的ALF。

Acetaminophen (APAP) overdose is the topmost cause of acute liver failure (ALF) in the United States, with N- acetylcysteine (NAC) as the only available pharmacological treatment. NAC is effective only in early presenting patients, but majority of these patients seek medical attention late. Thus, there is an unmet clinical need to explore alternative pharmacological approaches targeting later stages of ALF, such as by inhibiting progression of injury or by boosting the compensatory liver regeneration. Growth factor receptors, MET and EGFR, are considered essential for liver regeneration after partial hepatectomy (PH), but their roles in the clinically relevant model of APAP-induced liver injury (AILI) remain underexplored. Unlike PH, massive liver injury and inflammation during AILI greatly govern its pathophysiology and our previous studies have shown that roles of these growth factor receptors in AILI model cannot be presumed identical to that known in regeneration of a healthy liver after PH. In fact, our previously published study indicated an unexpected role of early EGFR activation in aggravating AILI, in contrast to its conventional role in hepatocyte proliferation during regeneration. We found that EGFR activation correlated with the severity of injury and treatment with EGFR inhibitor (canertinib) almost completely abolished AILI in mice. Contrary to EGFR, our preliminary studies indicate that MET is involved in actively suppressing progression of liver injury during AILI, apart from its role in promoting liver regeneration. Thus, our overarching hypothesis is that EGFR and MET play diametrically opposite roles in acute liver injury after APAP overdose, as opposed to their conventionally known and functionally similar roles in hepatocyte proliferation. In contrast to their similar roles in liver regeneration, MET directly suppresses and, paradoxically, EGFR aggravates acute liver injury in the AILI model. To establish the paradigm-shift proposed by our initial findings, our specific aims 1 and 2 will comprehensively investigate the roles of EGFR and MET, respectively, in liver injury and compensatory regeneration after APAP overdose, utilizing hepatocyte-specific knock out and receptor-activation strategies. Further, we will investigate the mechanisms underlying these novel roles of growth factor receptors in AILI. For therapeutic relevance, the effects of clinically-approved EGFR inhibitor (afatinib) and interventions targeting MET will be investigated on AILI, especially focusing on clinically relevant late intervention, when NAC is ineffective. Lastly, for human relevance, we will also investigate the effects of our interventions and validate mechanisms in well- characterized primary human hepatocyte model of AILI. These studies will not only elucidate regenerative role of MET and EGFR, for the first time in a clinically significant ALF model but will also reveal insights into the novel aspect of growth factor receptor biology related to acute liver injury. Moreover, successful completion of these studies will be useful to determine the potential of repurposing a clinically available EGFR inhibitor and/or interventions targeting MET to treat APAP-induced ALF.