Novel mechanisms stimulating liver repair after acetaminophen overdose

对乙酰氨基酚过量后刺激肝脏修复的新机制

• 批准号: 8863873
• 负责人: James P Luyendyk
• 金额: $ 35.21万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-10 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8863873
• 关键词: Acetaminophen; Acute; Acute Liver Failure; Affect; Albumins; Binding; Biochemistry; Biological Process; Clinic; Complement; Complement Activation; Data; Dissection; Dose; FDA approved; Gene Expression Regulation; Genetic; Goals; Hepatic; Hepatocyte; Hepatotoxicity; Human; Infection; Injury; Knockout Mice; Liver; Liver Failure; Liver Regeneration; Molecular; Monitor; Multiple Organ Failure; Mus; Mutate; N-acetyl-4-benzoquinoneimine; Organ failure; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacia brand of estropipate; Plasmin; Plasminogen; Plasminogen Activator Inhibitor 1; Play; Proteins; Proteolysis; Public Health; Publishing; Recombinants; Regenerative response; Research; Role; System; Testing; Time; Toxic effect; Tranexamic Acid; Translations; Tylenol; United States; Up-Regulation; Vitronectin; Wild Type Mouse; Work; acetaminophen overdose; base; chronic liver disease; inhibitor/antagonist; insight; liver cell proliferation; liver injury; liver repair; mouse model; novel; novel strategies; novel therapeutics; prevent; programs; public health relevance; response; small molecule

 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.

 描述（由申请人提供）： 对乙酰氨基酚 (APAP) 引起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首要原因。过去几十年来，治疗 APAP 过量患者的现有药理学策略进展甚微，仍然集中于降低药物的毒性。 反应性代谢产物NAPQI，从而降低APAP肝毒性。 APAP 的肝毒性反应被强大而及时的再生反应所抵消，再生反应旨在限制损伤进展并刺激肝细胞增殖。由于大多数患者在临床就诊时已经发生肝损伤，因此这些患者最有可能受益于在感染和器官衰竭等并发症出现之前刺激肝脏修复的治疗。然而，目前尚无法使用此类疗法，因为人们对 APAP 肝毒性后刺激和调节肝脏修复的机制知之甚少。我们强有力的初步研究表明，APAP 诱导的肝损伤和肝细胞增殖的进展是由纤溶酶（原）系统及其中枢调节剂纤溶酶原激活物抑制剂-1 (PAI-1) 控制的。这些研究的中心假设是，PAI-1 通过减少纤溶酶（原）驱动的蛋白水解来抑制 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脏修复。我们的方法包括转基因小鼠、具有定制活性的重组人 PAI-1 蛋白、新型小分子 PAI-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。研究小组由中毒性肝损伤和修复、PAI-1生物化学和功能以及急性和慢性肝病基因调控方面的专家组成。 慢性肝病。具体来说，我们将：（目标1）确定纤溶酶（原）激活加剧APAP诱导的肝损伤的机制； （目标2）确定PAI-1在APAP中毒后刺激肝脏修复的机制； （目标 3）确定 HIF-1a 调节的 PAI-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中毒性损伤后肝脏修复的理解，并强调预防 APAP 过量后肝衰竭的新治疗策略，包括 FDA 批准的纤溶酶（原）抑制剂的潜在重新利用和基于机制的重组人 PAI-1 蛋白的翻译，具有定制的活性以刺激肝脏再生。