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: 10440279
• 负责人: Elissa Everton
• 金额: $ 2.71万
• 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 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440279
• 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; acetaminophen-induced liver injury; 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.

抽象的 对乙酰氨基酚（乙酰 - para-氨基酚或APAP）是最常用的疼痛缓解剂 美国，但对乙酰氨基酚的过量是发达国家急性肝衰竭的主要原因。 目前，唯一可用的治疗方法是N-乙酰基半胱氨酸（NAC），仅有一个短窗口 有效性，或最终是肝移植。因此，治疗APAP过量的治疗替代方法是 在诊所需要急需。该建议将通过解密的机制来解决此问题 APAP引起的肝损伤和修复的性二态性，并通过 建立APAP过量后，两性男性的肝脏恢复如何加速。 性激素及其受体与在许多肝脏过程中驱动性二态性有关。 具体而言，女性中较高的平均生长激素（GH）分泌水平有助于较高的代谢 肝脏活动。与文献一致，我们的初步数据支持女性的较高抵抗力 小鼠到APAP，与肝坏死，细胞死亡减少和血清损伤标志物的检测相比显示 男性。此外，我们的单细胞RNA测序分析表明，雌性肝细胞和内皮细胞 （EC）比男性细胞表达的GH受体和GH途径激活的水平明显更高，而男性 炎症和细胞死亡途径的上调激活。为了准备此应用程序，我们 产生的初步数据表明，GH的治疗可显着，快速修复两种男性的组织 通过组织坏死，细胞死亡和小鼠存活来定量的亚剂量APAP之后的女性。 这些关键数据表明女性具有性二态肝再生优势，可以概括 GH治疗可诱导男性恢复并加速女性的康复。因此，我们假设 APAP灵敏度中存在性二态性，我们可以利用GH来利用 在男女中加速肝脏再生。在此提案中，我们将进一步研究GH及其其作用 通过单细胞RNA测序分析，APAP过量后，肝细胞和EC中的途径激活 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最佳 GH治疗，并鉴定出GH特异性剂量和每种性别的有效性时间以减轻肝脏 损伤和加速肝脏再生，对当前护理标准NAC具有较高的功效。潜在的 还将确定联合GH/NAC治疗的添加剂治疗作用。综上所述， 了解APAP引起的肝损伤中性差异背后的生物学机制，随后 再生和GH的调节将为建立GH疗法的生物基础提供治疗 两性中的APAP过量，目前未满足的临床需求。