Novel mechanisms stimulating liver repair after acetaminophen overdose

 描述（由申请人提供）：对乙酰氨基酚（APAP）诱导的肝损伤是一个主要的公共卫生问题，也是美国急性肝衰竭的头号原因。用于管理APAP过量患者的现有药理学策略在过去几十年中发展得很少，并且仍然专注于降低药物的毒性。 活性代谢物NAPQI，从而降低APAP肝毒性。对APAP的肝毒性反应被旨在限制损伤进展和刺激肝细胞增殖的稳健和及时的再生反应所抵消。由于大多数患者在临床上出现时已经发生了肝损伤，因此这些患者最有可能在感染和器官衰竭等并发症发生之前受益于旨在刺激肝脏修复的治疗。然而，这种疗法目前还不可用，因为对APAP肝毒性后刺激和调节肝脏修复的机制知之甚少。我们的初步研究表明，APAP诱导的肝损伤和肝细胞增殖的进展是由纤溶酶（原）系统及其中枢调节因子纤溶酶原激活物抑制剂-1（派-1）控制的。这些研究的核心假设是派-1通过减少纤溶酶（原）驱动的蛋白水解抑制APAP肝毒性的放大，并通过其抗蛋白酶和/或玻连蛋白结合活性刺激肝修复。我们的方法包括基因修饰小鼠、具有定制活性的重组人派-1蛋白、新型小分子派-1抑制剂和FDA批准的纤溶酶原激活抑制剂（氨甲环酸）的组合。该研究小组由中毒性肝损伤和修复、派-1生物化学和功能以及急性和慢性肝损伤中的基因调控方面的专家组成。 慢性肝病具体而言，我们将：（目的1）确定纤溶酶（原）激活加剧APAP诱导的肝损伤的机制;（目的2）确定派-1刺激APAP毒性后肝修复的机制;和（目的3）确定HIF-1a调节的派-1诱导在APAP过量后肝损伤和修复中的作用。所获得的见解将显着推进目前对毒性利耶损伤后肝修复的理解，并强调预防APAP过量后肝功能衰竭的新治疗策略，包括FDA批准的纤溶酶（原）抑制剂的潜在再利用和重组人派-1蛋白的基于机制的翻译，具有定制的活性以刺激肝再生。

 DESCRIPTION (provided by applicant): Acetaminophen (APAP)-induced liver injury is a leading public health concern and the number one cause of acute liver failure in the United States. Existing pharmacologic strategies for the management of APAP overdose patients have evolved very little in the last several decades, and remain focused on reducing the toxicity of the reactive metabolite NAPQI, thereby reducing APAP hepatotoxicity. The hepatotoxic response to APAP is counterbalanced by a robust and timely regenerative response aimed at limiting progression of injury and stimulating hepatocyte proliferation. Because liver injury has already occurred at the time most patients are seen clinically, these patients would most likely benefit from therapies aimed at stimulating liver repair prior to the onset of complications such as infection and organ failure. However, such therapies are not currently available because the mechanisms that stimulate and regulate liver repair after APAP hepatotoxicity are poorly understood. Our strong preliminary studies indicate that the progression of APAP-induced liver injury and hepatocyte proliferation are controlled by the plasmin (ogen) system and its central regulator plasminogen activator inhibitor-1 (PAI-1). The central hypothesis framing these studies is that PAI-1 inhibits amplification of APAP hepatotoxicity by reducing plasmin (ogen)-driven proteolysis, and stimulates liver repair by its anti- protease and/or vitronectin-binding activitie. Our approach includes a combination of genetically-modified mice, recombinant human PAI-1 proteins with customized activities, novel small molecule PAI-1 inhibitors, and an FDA-approved inhibitor of plasminogen activation (tranexamic acid). The investigative team comprises experts in toxic liver injury and repair, PAI-1 biochemistry and function, and gene-regulation in acute and chronic liver disease. Specifically, we will: (Aim 1) Determine the mechanism whereby plasmin(ogen) activation exacerbates APAP-induced liver injury; (Aim 2) Determine the mechanism whereby PAI-1 stimulates liver repair after APAP toxicity; and (Aim 3) Determine the role of HIF-1a-regulated PAI-1 induction in liver injury and repair after APAP overdose. The insights gained will significantly advance the current understanding of liver repair after toxic lier injury, and highlight novel therapeutic strategies to prevent liver failure after APAP overdose, including potential repurposing of FDA-approved plasmin (ogen) inhibitors and mechanism-based translation of recombinant human PAI-1 proteins with customized activity to stimulate liver regeneration.