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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.

项目摘要对乙酰氨基酚（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。虽然目前的解毒剂N-乙酰半胱氨酸（NAC）是在2000年开发的， 1970年代，如果早期给药有效，如果在APAP后超过8小时给药，其疗效会降低服药过量尽管对APAP诱导的肝损伤机制的理解取得了重大进展，在随后的几十年中，没有开发出补充NAC的其他治疗方法，翻译到诊所部分问题是病人延迟到医院就诊，损伤过程通常是在进行中的，并且任何针对早期过程的药物（包括NAC）可能是有限的，效益现在认识到，APAP诱导的损伤后肝脏的再生能力是一个重要因素。决定患者预后的关键特征。APAP诱导晚期先天性免疫反应以响应细胞免疫应答。损伤，我们在小鼠和人类中的早期研究表明，免疫细胞浸润促进了破坏细胞，有助于再生和恢复。我们最近公布的数据表明，引导信号如netrin-1蛋白通过腺苷A2 B受体发挥作用，中性粒细胞和增强巨噬细胞浸润到坏死区域，以促进肝再生， APAP过量后的康复根据最近的信息，中性粒细胞和巨噬细胞表型可以将细胞功能从促炎性转变为抗炎性，我们假设，腺苷A2 B受体增强APAP过量后免疫细胞介导的肝脏恢复，一种有效的针对APAP诱导的肝毒性的迟效治疗方法。这一假设将是通过1）阐明参与巨噬细胞募集和肝再生的分子机制进行测试在腺苷A2 B受体活化和它们在体内APAP过量后的恢复促进后，2）检查药理学调节以及腺苷A2 B受体缺乏对 APAP诱导的体内肝损伤，以及3）探索A2 BAR激动剂和天然免疫应答的作用并评估APAP过量后患者的循环单核细胞标志物。我们有 APAP过量的先进早期作用替代疗法，如4-甲基吡唑（4 MP），通过预临床动物实验和志愿者安全性研究，以规划临床试验。虽然4 MP功能预防APAP诱导的损伤，并对严重过量的患者有益，预计本文提出的研究结果将为A2 B受体作为一种假定的靶点提供新的见解，在临床中补充4 MP和NAC并改善APAP后结局的迟效治疗服药过量