Sexual dimorphism of acetaminophen-induced liver injury and regeneration

对乙酰氨基酚诱导的肝损伤和再生的性别二态性

• 批准号: 10315150
• 负责人: Elissa Everton
• 金额: $ 4.6万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315150
• 关键词: Acceleration; Acetaminophen; Acute Liver Failure; Address; Albumins; American; Aminophenols; Analgesic and Antipyretic; Analgesics; Anti-Inflammatory Agents; Architecture; Automobile Driving; Binding; Biological; Biological Assay; CYP2E1 gene; Cell Cycle; Cell Death; Cells; Clinic; Clinical; Consumption; Country; Cysteine; Cytochromes; Data; Detection; Dose; Effectiveness; Endothelial Cells; Female; Foundations; Glutathione; Goals; Gonadal Steroid Hormones; Growth Hormone Receptor; Hepatocyte; Hepatotoxicity; Hormone secretion; Hormones; Hour; Imines; Inflammatory; Injections; Injury; Intoxication; Knock-out; Literature; Liver; Liver Failure; Liver Regeneration; Liver diseases; Mediating; Metabolic; Metabolic Pathway; Mus; Natural regeneration; Organ; Overdose; Pathway interactions; Pharmaceutical Preparations; Preparation; Process; Receptor Activation; Recovery; Resistance; Role; Serum; Somatotropin; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Treatment Efficacy; United States; acetaminophen overdose; alternative treatment; cadherin 5; cell type; differential expression; exhaust; hepatic necrosis; hormone therapy; injury and repair; liver injury; liver repair; liver transplantation; male; necrotic tissue; novel therapeutic intervention; para-benzoquinone; receptor; regenerative; restoration; sex; sexual dimorphism; sexual disparity; single-cell RNA sequencing; standard care; standard of care; tissue repair; treatment comparison; urinary

ABSTRACT Acetaminophen (acetyl-para-aminophenol or APAP) is the most commonly used pain reliever in the United States, yet acetaminophen overdose is the leading cause of acute liver failure in the developed world. Currently the only available treatments are N-acetyl cysteine (NAC), which only has a short window of effectiveness, or ultimately liver transplant. Therefore, therapeutic alternatives to treat APAP overdose are urgently needed in the clinic. This proposal will address this issue by deciphering the mechanisms of sexual dimorphism of APAP-induced liver injury and repair, and to leverage this sexual dimorphism by establishing how hormone therapy will accelerate liver recovery in both sexes following APAP overdose. Sex hormones and their receptors have been implicated in driving sexual dimorphism in many liver processes. Specifically, higher average levels of growth hormone (GH) secretion in females contributes to higher metabolic activity in their livers. Consistent with the literature, our preliminary data support the higher resistance of female mice to APAP, shown by reduced liver necrosis, cell death, and detection of serum injury markers compared to males. Moreover, our single-cell RNA sequencing analyses reveal that female hepatocytes and endothelial cells (ECs) express significantly higher levels of GH receptor and GH pathway activation than male cells, while males have upregulated inflammatory and cell death pathway activation. In preparation for this application, we generated preliminary data showing that GH treatment significantly and rapidly repairs the tissues of both males and females following sub-lethal doses of APAP, as quantified by tissue necrosis, cell death, and mouse survival. These key data suggest a sexually dimorphic liver regenerative advantage in females, which can be recapitulated with GH treatment to induce recovery in males and accelerate recovery in females. Therefore, we hypothesize that there is a sexual dimorphism in APAP sensitivity that we can leverage with the use of GH to accelerate liver regeneration in both sexes. In this proposal, we will further examine the role of GH and its pathway activation in hepatocytes and ECs following APAP overdose via single-cell RNA sequencing analysis and hepatocyte and EC -specific GH receptor knockouts. We will leverage these findings to establish an optimal GH therapy with identification of GH specific doses and time frame of effectiveness for each sex to mitigate liver injury and accelerate liver regeneration with superior efficacy to the current standard-of-care NAC. Potential additive therapeutic effect of combined GH/NAC treatment will be also determined. In conclusion, understanding the biological mechanisms behind the sexual disparity in APAP-induced liver injury, subsequent regeneration, and modulation by GH will provide the biological foundation to establish a GH therapy to treat APAP overdose in both sexes, a currently unmet clinical need.

摘要 对乙酰氨基酚（乙酰对氨基酚或APAP）是最常用的止痛药， 然而，在发达国家，对乙酰氨基酚过量是急性肝功能衰竭的主要原因。 目前唯一可用的治疗方法是N-乙酰半胱氨酸（NAC），其只有很短的时间窗， 有效性，或最终肝移植。因此，治疗APAP过量的替代疗法是 诊所急需的。该提案将通过破译以下机制来解决这一问题： APAP诱导的肝损伤和修复的性别二型性，并通过以下方式利用这种性别二型性 确定激素治疗如何加速APAP过量后两性的肝脏恢复。 性激素及其受体在许多肝脏过程中参与驱动性二型性。 具体而言，女性生长激素（GH）分泌的平均水平较高， 活动在他们的肝脏。与文献一致，我们的初步数据支持女性的抵抗力更高， 小鼠对APAP，显示减少肝坏死，细胞死亡，并检测血清损伤标志物相比， 男性。此外，我们的单细胞RNA测序分析显示，女性肝细胞和内皮细胞 (ECs)表达显著高于男性细胞的GH受体和GH途径活化水平，而男性细胞表达显著高于男性细胞的GH受体和GH途径活化水平。 具有上调的炎症和细胞死亡途径激活。在准备此应用程序时，我们 产生的初步数据显示，生长激素治疗显着和迅速修复组织的两个男性 和雌性动物在亚致死剂量的APAP后，如通过组织坏死、细胞死亡和小鼠存活来量化的。 这些关键数据表明，女性的性二态性肝脏再生优势，这可以概括为 GH治疗以诱导雄性动物恢复并加速雌性动物恢复。因此，我们假设 在APAP敏感性中存在性别二态性，我们可以利用GH来 加速两性的肝再生。在这项建议中，我们会进一步研究生长激素的作用， 通过单细胞RNA测序分析APAP过量后肝细胞和EC中的通路活化 以及肝细胞和EC特异性GH受体敲除。我们将利用这些发现来建立一个最佳的 GH治疗，确定每种性别的GH特异性剂量和有效性时间范围，以减轻肝脏 损伤和加速肝再生，具有优于当前护理标准NAC的功效。潜在 还将确定GH/NAC联合治疗的附加治疗效果。最后，我谨指出， 了解APAP诱导的肝损伤中性别差异背后的生物学机制，随后 生长激素的再生和调节将为建立生长激素治疗提供生物学基础， 两种性别的APAP过量，目前尚未满足临床需求。