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: 9558268
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9558268
• 关键词: Ablation; Acetaminophen; Acetylcysteine; Acute Liver Failure; Analgesics; Animal Model; Anti-inflammatory; Blood specimen; CRISPR/Cas technology; Cells; Clinical; Complex; Cysteine; Data; Disease; Disease Outcome; Disease Progression; Dose; 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; addiction; base; chronic pain; clinically relevant; cytokine; defined contribution; immune checkpoint; immunoregulation; improved; improved outcome; injured; liver injury; macrophage; mortality; new therapeutic target; novel; prescription opioid; response; scavenger receptor; standard of care; targeted treatment; 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