Innate Pattern Recognition Receptor and Acetaminophen-induced Liver Injury

先天模式识别受体和对乙酰氨基酚诱导的肝损伤

• 批准号: 10612390
• 负责人: Xiang-Yang Shawn Wang
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10612390
• 关键词: Ablation; Accidents; Acetaminophen; Acetylcysteine; Acute Liver Failure; Analgesics; Animal Model; Anti-Inflammatory Agents; Blood specimen; CRISPR/Cas technology; Cells; Clinical; Complex; Cysteine; Cytoprotection; Data; Deterioration; Disease; Disease Outcome; Disease Progression; Dose; Drug Prescriptions; Drug usage; Elements; Epidemic; Family; Genetic; Genetic Models; HMGB1 gene; Healthcare; Hepatic; Hepatocyte; Hepatotoxicity; Homeostasis; Human; IL10 gene; IL17 gene; Immune; Immune Targeting; Immune response; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Intervention; Kupffer Cells; Liver; Macrophage; Mediator; Medicine; Mental Health; Metabolic Activation; Metabolism; Military Medicine; Molecular; Mus; Myeloid Cells; Narcotics; Natural Immunity; Opioid Analgesics; Overdose; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Pattern; Pattern Recognition; Pattern recognition receptor; Pharmaceutical Preparations; Phenotype; Physiological; Population; Process; Production; Rationalization; Research; Risk; Risk Factors; Role; Sentinel; Severities; Shapes; Signal Transduction; Specimen; Sterility; Stress; Surveys; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toll-like receptors; Transcriptional Regulation; Veterans; Work; acetaminophen overdose; acetaminophen-induced liver injury; acute drug induced liver toxicity; addiction; chronic pain; clinically relevant; cytokine; defined contribution; drug induced liver injury; feasibility testing; hepatocyte injury; hepatoprotective; immune checkpoint; immunoregulation; improved; improved outcome; liver inflammation; liver injury; military veteran; mortality; new therapeutic target; novel; prescription opioid; response; scavenger receptor; standard of care; targeted treatment; tissue injury; tissue stress; γδ T cells

Hepatotoxicity induced by acetaminophen (APAP) has become the leading cause of acute liver failure among the general and the VA populations. The APAP overdose or abuse causing severe liver injury remains a great threat to veterans. Currently, the standard of care implemented uses high doses of the L-cysteine precursor N-Acetylcysteine (NAC) making it the only treatment option for patients that suffer from APAP-induced liver injury (AILI). Unfortunately, the therapeutic window of NAC administration between overdose and treatment is narrow leaving many patients with no other recourses. The focus of research in understanding the pathologic mechanisms of AILI has been always on intracellular changes in hepatocytes. However, emerging evidence suggests a critical role of sterile inflammation for modifying the outcome of disease progression. Our preliminary studies showed that ablation of scavenger receptor A (SRA), an innate pattern recognition receptor primarily expressed on myeloid cells, e.g., Kupffer cells (KCs), exacerbated AILI indicated by sharply increased mortality and hepatic inflammation. This was associated with markedly reduced production of anti-inflammatory cytokine IL-10. SRA expression also positively correlates with IL-10 levels in human blood samples after APAP exposure. SRA-IL-10 pathway regulates a sophisticated inflammatory cascade including activation of unconventional γδ T cells that are known to aggravate tissue damage. Our central hypothesis is that SRA acts as a master regulator of hepatic immunity and promotes liver homeostasis in AILI. The objective of this project is to interrogate and mechanistically understand SRA as a key hepatic immune `checkpoint' that operates in highly integrated immune processes during AILI. These include KC response to damage-associated molecular patterns released from injured hepatocytes, modulation of hepatocyte-intrinsic stress signaling, and mobilization of pathogenic inflammatory cells. Analyses of clinical specimens from APAP overdose patients for immune alterations will also be performed to validate our findings in animal models. Furthermore, we will test the feasibility of targeting SRA- regulated immune network to improve NAC treatment of AILI. Successful completion of this research will advance our understanding of a novel hepatocyte-extrinsic immunologic mechanism of AILI. It is anticipated that a crucial role of SRA, as a previously unrecognized immune determinant of AILI, will be established for the first time. Given an increased risk of drug overdose or abuse among veterans, our research is highly significant and clinically relevant to the healthcare of veterans. Elucidating the key elements and molecular pathways that define the pathogenesis of AILI not only will help identify risk factors to decrease the incidence of AILI, but also provide new opportunities to develop novel immune-targeted therapies that benefit the large population of veterans.

对乙酰氨基酚（acetaminophen，APAP）引起的肝毒性已成为急性肝衰竭的主要原因 在普通人和退伍军人中APAP过量或滥用导致严重肝损伤仍然是一个问题。 对退伍军人的巨大威胁。目前，实施的护理标准使用高剂量的L-半胱氨酸前体 N-乙酰半胱氨酸（NAC）使其成为APAP诱导的肝损伤患者的唯一治疗选择 （AILI）.不幸的是，NAC给药在过量和治疗之间的治疗窗口很窄 使许多病人没有其他的资源。研究的重点是了解病理性 AILI的机制一直是肝细胞内的变化。然而，新出现的证据表明， 提示无菌性炎症对改变疾病进展结果的关键作用。我们的初步 研究表明，清除清道夫受体A（SRA），一种先天性模式识别受体， 在骨髓细胞上表达，例如，枯否细胞（KCs），加重AILI，表现为死亡率急剧增加 和肝脏炎症。这与抗炎细胞因子的产生显著减少有关 IL-10。在APAP暴露后，SRA表达也与人血液样品中的IL-10水平正相关。 SRA-IL-10通路调节复杂的炎症级联反应，包括非常规γδ T的激活 这些细胞会加重组织损伤我们的中心假设是SRA作为一个主调节器 肝脏免疫和促进肝脏稳态在AILI。该项目的目的是询问和 机械地将SRA理解为在高度整合的免疫系统中起作用的关键肝脏免疫“检查点”， 在AILI过程中。这些包括KC对损伤相关分子模式的反应， 损伤的肝细胞，肝细胞内在应激信号传导的调节，以及致病性 炎症细胞对APAP过量患者的临床标本进行免疫改变分析， 来验证我们在动物模型中的发现。此外，我们将测试针对SRA的可行性- 调节免疫网络以改善AILI的NAC治疗。这项研究的成功完成将 进一步了解AILI的一种新的肝细胞外源性免疫机制。预计各国 SRA作为一种以前未被认识到的AILI免疫决定因子，其关键作用将首先被确定， 时间鉴于退伍军人吸毒过量或滥用药物的风险增加，我们的研究非常重要， 临床上与退伍军人的医疗保健相关。阐明了决定 对AILI发病机制的研究，不仅有助于明确AILI的危险因素，降低AILI的发病率， 开发新型免疫靶向疗法的新机会，使大量退伍军人受益。