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：
10211897
负责人：
Anup Ramachandran
金额：
$ 33.88万
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/10211897
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 physiology 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 Mediating Molecular Mus NTN1 gene Natural regeneration Necrosis Neutrophil Infiltration Overdose Patients Pharmaceutical Preparations Pharmacology Phenotype Process Prognosis Property Proteins Publishing Recovery Regenerative capacity Reperfusion Injury Resolution Role Techniques Testing Therapeutic Therapeutic Intervention Time Translating Translations Tumor-infiltrating immune cells United States Up-Regulation Western World Work acetaminophen overdose base cell injury clinically relevant cytokine fomepizole hepatic necrosis immunoreaction improved outcome in vivo insight liver injury liver ischemia macrophage monocyte neutrophil novel novel strategies 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。尽管当前的解毒剂N-乙酰半胱氨酸（NAC）在 1970年代，如果提早给药，则有效，如果给出APAP后8小时以上，其功效会降低过量。尽管在理解APAP诱导的肝损伤机制方面取得了重大进展随后的几十年，未开发其他其他治疗方法，并且翻译成诊所。问题的一部分是将患者延迟出现到医院，此时伤害过程通常正在进行中，任何包括NAC靶向早期过程在内的药物可能有限益处。现在已经认识到，APAP诱导后的肝脏的再生能力是决定患者预后的关键特征。 APAP响应细胞诱导了晚期先天免疫反应受伤，我们对小鼠和人类的早期研究表明，免疫细胞浸润促进了去除细胞受损，有助于再生和恢复。我们最近发布的数据现在表明引导线索，例如通过腺苷A2B受体蛋白Netrin-1功能抑制中性粒细胞并增强巨噬细胞浸润到坏死区，以促进肝脏再生和 APAP过量后恢复。基于中性粒细胞和巨噬细胞表型的最新信息可以将细胞功能从促炎性转移到抗炎，我们假设激活腺苷A2B受体增强了APAP过量后免疫细胞介导的肝脏回收，这可能是一种有效的晚期作用治疗方法，可针对APAP诱导的肝毒性。这个假设将是通过1）阐明参与巨噬细胞募集和肝脏再生的分子机制激活腺苷A2b受体及其在体内过量过量后恢复后的促进后，2）检查药理学调节的影响以及腺苷A2B受体对 APAP引起的体内肝损伤，3）探索A2BAR激动剂和先天免疫反应的作用延长NAC并评估APAP过量后患者的循环单核细胞标记。我们有高级早期作用替代替代疗法，用于APAP过量，例如4-甲基吡唑（4MP）临床动物实验和志愿者安全研究，以计划临床试验。而4MP功能预防APAP诱导的损伤，对严重过量的患者有益，预计此处提出的研究的结果将为A2B受体提供新的见解，作为A的推定目标在诊所中以4MP和NAC的补充，并在APAP后改善预后过量。