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: 10427222
• 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/10427222
• 关键词: Ablation; Acetaminophen; Acetylcysteine; Acute Liver Failure; Analgesics; Animal Model; Anti-Inflammatory Agents; Blood specimen; CRISPR/Cas technology; Cells; Clinical; Complex; Cysteine; Data; Disease; Disease Outcome; Disease Progression; Dose; Drug Prescriptions; Drug usage; Elements; Epidemic; Family; Genetic; Genetic Models; HMGB1 Protein; Healthcare; Hepatic; Hepatocyte; Hepatotoxicity; Homeostasis; Human; IL10 gene; Immune; Immune Targeting; Immune response; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-17; Intervention; Kupffer Cells; Lead; Light; Liver; Mediator of activation protein; 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; 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; addiction; base; chronic pain; clinically relevant; cytokine; defined contribution; drug induced liver injury; feasibility testing; hepatocyte injury; immune checkpoint; immunoregulation; improved; improved outcome; liver inflammation; liver injury; macrophage; 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（APAP）引起的肝毒性已成为急性肝衰竭的主要原因 在普通人群和退伍军人管理局人群中。 APAP 过量或滥用导致严重肝损伤仍然是一个 对退伍军人来说威胁很大。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 引起的肝损伤患者的唯一治疗选择 （艾力）。不幸的是，NAC 给药过量和治疗之间的治疗窗口很窄 使许多患者别无选择。研究重点是了解病理学 AILI的发生机制一直与肝细胞的细胞内变化有关。然而，不断出现的证据 表明无菌炎症对于改变疾病进展的结果具有关键作用。我们的初步 研究表明，清道夫受体 A (SRA)（一种先天模式识别受体）的消融主要 在骨髓细胞（例如库普弗细胞 (KC)）上表达，死亡率急剧增加，从而加剧 AILI 和肝脏炎症。这与抗炎细胞因子的产生显着减少有关 IL-10。 SRA 表达还与 APAP 暴露后人体血液样本中 IL-10 水平呈正相关。 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 已知会加剧组织损伤的细胞。我们的中心假设是 SRA 充当主监管者 肝脏免疫并促进 AILI 中的肝脏稳态。该项目的目的是询问和 从机制上理解 SRA 作为一个关键的肝脏免疫“检查点”，在高度整合的免疫中发挥作用 AILI 期间的流程。其中包括 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的调节以及病原菌的动员 炎症细胞。对 APAP 过量患者的临床标本进行免疫改变分析也将 进行以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 NAC 对 AILI 的治疗。这项研究的成功完成将 促进我们对 AILI 的新型肝细胞外源性免疫机制的理解。预计 SRA 作为 AILI 的一个以前未被认识的免疫决定因素，其至关重要的作用将首次被确立 时间。鉴于退伍军人服用药物过量或滥用的风险增加，我们的研究非常重要 与退伍军人的医疗保健临床相关。阐明定义的关键要素和分子途径 AILI 的发病机制不仅有助于识别危险因素以降低 AILI 的发生率，还可以提供 开发新型免疫靶向疗法的新机会，使大量退伍军人受益。