The Immune Response After Drug Induced Hepatotoxicity

药物引起的肝毒性后的免疫反应

基本信息

批准号：
10541895
负责人：
Anup Ramachandran
金额：
$ 34.1万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541895
关键词：
Acetaminophen Acetylcysteine Acute Liver Failure Adenosine A2B Receptor Agonist Alternative Therapies Animal Experiments Anti-Inflammatory Agents Antidotes Area Biochemistry Blood specimen Cell Death Cell Survival Cells Cellular biology Central Vein Clinic Clinical Clinical Trials Complement Complement component C4 Cues Data Development Equilibrium Event Excision Functional disorder Gene Expression Genetic Goals Hepatocyte Hepatotoxicity Hospitals Hour Human Immune Immune response Infiltration Inflammatory Injury Innate Immune Response Innate Immune System Intervention Laboratories Literature Liver Liver Regeneration Macrophage Mediating Molecular Mus NTN1 gene Natural regeneration Necrosis Neutrophil Infiltration Overdose Patients Pharmaceutical Preparations Phenotype Process Property Proteins Publishing Recovery Regenerative capacity Reperfusion Injury Resolution Role Techniques Testing Therapeutic Therapeutic Intervention Time Translating Translations United States Up-Regulation Western World Work acetaminophen overdose acetaminophen-induced liver injury cell injury clinically relevant cytokine drug induced liver injury drug repurposing fomepizole hepatic necrosis immune cell infiltrate immunoreaction immunoregulation improved outcome in vivo insight liver ischemia monocyte neutrophil novel novel strategies patient prognosis pharmacologic pre-clinical prevent receptor recruit repaired response safety study single-cell RNA sequencing spatiotemporal standard of care volunteer

项目摘要

PROJECT SUMMARY Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and thus is an important clinical problem. Though the current antidote N-acetylcysteine (NAC) was developed in the 1970's and is effective if administered early, its efficacy decreases if given beyond 8 hours after an APAP overdose. In spite of the significant progress in understanding mechanisms of APAP-induced liver injury in the subsequent decades, no additional therapeutic approaches to complement NAC have been developed and translated to the clinic. Part of the problem is the delayed presentation of patients to the hospital, by which time the injury process is often in progress and any drugs including NAC targeting early processes may be of limited benefit. It is now recognized that the regenerative capacity of the liver subsequent to APAP-induced injury is a critical feature dictating patient prognosis. APAP induces a late innate immune reaction in response to cell injury, and our early studies in mice and humans indicated that immune cell infiltration facilitated removal of damaged cells and was helpful in regeneration and recovery. Our recently published data now indicate that guidance cues such as the protein netrin-1 function through the adenosine A2B receptor to suppress neutrophils and enhance macrophage infiltration into the necrotic area to facilitate liver regeneration and recovery after an APAP overdose. Based on recent information that neutrophil and macrophage phenotypes can shift cell functionality from pro-inflammatory to anti-inflammatory, we hypothesize that activation of the adenosine A2B receptor enhances immune-cell mediated liver recovery after APAP overdose and this could be an effective late-acting therapeutic approach against APAP-induced hepatotoxicity. This hypothesis will be tested by 1) Elucidating molecular mechanisms involved in macrophage recruitment and liver regeneration after activation of the adenosine A2B receptor and their facilitation of recovery after APAP overdose in vivo, 2) Examining the effects of pharmacological modulation as well as deficiency of the adenosine A2B receptor on APAP-induced liver injury in vivo, and 3) Explore the role of A2BAR agonists and the innate immune response after prolonged NAC and evaluate circulating monocyte markers from patients after APAP overdose. We have advanced early acting alternative therapies for APAP overdose such as 4-methylpyrazole (4MP) through pre- clinical animal experiments and volunteer safety studies to planning of a clinical trial. While 4MP functions to prevent APAP-induced injury and would be beneficial in patients with severe overdose, it is anticipated that results from the studies proposed here will provide novel insight into the A2B receptor as a putative target for a late acting therapeutic to complement 4MP and NAC in the clinic and improve outcomes after an APAP overdose.

项目概要对乙酰氨基酚 (APAP) 过量是美国急性肝衰竭的最常见原因因此是一个重要的临床问题。尽管目前的解毒剂 N-乙酰半胱氨酸 (NAC) 是在 1970 年代，如果早期给药有效，如果在 APAP 后超过 8 小时给药，其疗效会降低过量。尽管在理解 APAP 诱导的肝损伤机制方面取得了重大进展在接下来的几十年里，没有开发出额外的治疗方法来补充 NAC，并且翻译到诊所。部分问题是患者到医院的时间被延迟，而到那时损伤过程通常正在进行中，任何针对早期过程的药物（包括 NAC）的作用可能有限益处。现在人们认识到 APAP 引起的损伤后肝脏的再生能力是决定患者预后的关键特征。 APAP 诱导针对细胞的晚期先天免疫反应损伤，我们对小鼠和人类的早期研究表明，免疫细胞浸润有助于去除受损细胞，有助于再生和恢复。我们最近发布的数据表明指导信号，如蛋白质 netrin-1 通过腺苷 A2B 受体发挥作用，抑制中性粒细胞并增强巨噬细胞浸润坏死区域，以促进肝脏再生和 APAP 过量后的恢复。根据最近的信息，中性粒细胞和巨噬细胞表型可以将细胞功能从促炎转变为抗炎，我们假设腺苷 A2B 受体可增强 APAP 过量后免疫细胞介导的肝脏恢复，这可能是一种针对 APAP 诱导的肝毒性的有效晚效治疗方法。这个假设将是测试通过 1) 阐明参与巨噬细胞募集和肝再生的分子机制体内 APAP 过量后激活腺苷 A2B 受体并促进其恢复，2) 检查药理调节以及腺苷 A2B 受体缺乏对 APAP诱导的体内肝损伤，以及3）探索A2BAR激动剂的作用和先天免疫反应延长 NAC 后并评估 APAP 过量后患者的循环单核细胞标记物。我们有针对 APAP 过量的先进早期作用替代疗法，例如 4-甲基吡唑 (4MP) 临床动物实验和志愿者安全研究到临床试验的规划。虽然 4MP 的功能是预防 APAP 引起的损伤，并且对严重过量服用的患者有益，预计这里提出的研究结果将为 A2B 受体作为推定靶点提供新的见解。晚效疗法可补充临床中的 4MP 和 NAC，并改善 APAP 后的预后过量。