Interactions between neutrophils and cholangiocytes in alcoholic hepatitis

酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用

基本信息

批准号：
10494268
负责人：
MICHAEL H NATHANSON
金额：
$ 65.8万
依托单位：
YALE UNIVERSITY
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：
2021-09-25 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10494268
关键词：
Affect Alcoholic Hepatitis Alcoholic Liver Diseases Animal Model Apoptosis Attenuated Bicarbonates Bile Duct Epithelium Bile fluid Biliary Biliary Atresia Calcium Calcium Channel Cholestasis Clinical Complication Data Defect Development Disease Ductal Epithelial Cell Etiology Frequencies Functional disorder Hepatic lobule Hepatitis C Hepatocellular Damage Hepatocyte Human Impairment Inositol Lead Leukocytes Life Liquid substance Liver diseases Mediating Molecular Neutrophil Infiltration Obstruction Organoids Pathogenesis Pathogenicity Pathway interactions Patients Play Primary biliary cirrhosis Process Prognosis Protein Isoforms Publications Role Serum Signal Pathway Steroids Testing Transaminases Work base bile duct cell type cholangiocyte hepatocellular injury improved liver biopsy liver injury mortality neutrophil new therapeutic target novel therapeutics primary sclerosing cholangitis receptor receptor expression targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT Alcoholic hepatitis is a serious and potentially life-threatening complication of alcoholic liver disease, with a short-term mortality as high as 20-50%. Traditionally, alcoholic hepatitis is thought to result mostly from hepatocellular damage. However, recent evidence suggests that alcoholic hepatitis also results in cholestatic liver injury, and that worsening cholestasis in fact is associated with a worse prognosis. This is an important concept because cholestasis generally is a separate process from hepatocellular injury, and so its presence may suggest previously unappreciated pathogenic mechanisms and potential therapeutic targets. Cholestasis may reflect impaired secretory function of hepatocytes, but often instead reflects impaired secretion by bile duct epithelial cells, or cholangiocytes. A variety of liver diseases are largely or entirely due to cholangiocyte damage or dysfunction, and these cholangiopathies are characterized by cholestasis. Despite their widely different etiologies, loss of expression of type 3 inositol trisphosphate receptors (ITPR3) from cholangiocytes is a final common pathway among the cholangiopathies that results in cholestasis. ITPR3 plays this important role because it is the primary intracellular calcium release channel in cholangiocytes, and its expression is necessary to mediate biliary fluid and bicarbonate secretion. This project will investigate the idea that cholangiocytes are involved in the cholestasis that occurs in alcoholic hepatitis and that, as in other cholangiopathies, this also is due to loss of ITPR3. In particular, this project will test the hypothesis that the cholestatic changes that occur in alcoholic hepatitis are due in part to direct interactions between cholangiocytes and neutrophils. Moreover, the relative contribution of cholangiocytes and hepatocytes to cholestasis will be determined. This will be tested through three specific aims: (1) We will determine whether and why the neutrophils in alcoholic hepatitis behave abnormally towards cholangiocytes; (2) We will determine whether and why the cholangiocytes in alcoholic hepatitis have intrinsic secretory defects; and (3) We will identify targets for therapy based on the mechanism(s) of neutrophil-cholangiocyte interactions. This project has the potential to fundamentally shift our understanding of alcoholic hepatitis, by establishing a new role for cholangiocytes in this disease and by determining how neutrophils interact with them to cause cholestasis. Such a paradigm shift in our understanding of the molecular pathogenesis of this disorder may in turn define new targets for therapy. Considering that no new therapy for alcoholic hepatitis has been shown to be efficacious since the use of steroids was introduced 40 years ago, this work has the potential to fundamentally alter the approach to patients with this life-threatening illness.

项目概要/摘要酒精性肝炎是酒精性肝病的一种严重且可能危及生命的并发症，短期死亡率高达20-50%。传统上，酒精性肝炎被认为主要是由肝细胞损伤。然而，最近的证据表明酒精性肝炎也会导致胆汁淤积肝损伤，而胆汁淤积恶化实际上与更差的预后相关。这是一个重要的这个概念是因为胆汁淤积通常是与肝细胞损伤不同的过程，因此它的存在可能提示以前未认识到的致病机制和潜在的治疗靶点。胆汁淤积可能反映肝细胞分泌功能受损，但通常反映胆汁分泌功能受损导管上皮细胞或胆管细胞。多种肝脏疾病很大程度上或完全是由胆管细胞引起的损伤或功能障碍，这些胆管病的特征是胆汁淤积。尽管他们广泛根据不同的病因，胆管细胞中 3 型肌醇三磷酸受体 (ITPR3) 表达的丧失是导致胆汁淤积的胆管病的最终共同途径。 ITPR3 发挥着如此重要的作用的作用，因为它是胆管细胞中主要的细胞内钙释放通道，其表达为介导胆汁和碳酸氢盐分泌所必需的。该项目将研究以下想法：胆管细胞参与酒精性肝炎中发生的胆汁淤积，并且与其他肝炎一样胆管病，这也是由于 ITPR3 缺失所致。特别是，该项目将检验以下假设：酒精性肝炎中发生的胆汁淤积变化部分是由于之间的直接相互作用胆管细胞和中性粒细胞。此外，胆管细胞和肝细胞对即可确定胆汁淤积。这将通过三个具体目标进行测试：（1）我们将确定是否以及为什么酒精性肝炎中的中性粒细胞对胆管细胞的行为异常； (2) 我们将确定酒精性肝炎中的胆管细胞是否以及为何存在内在的分泌缺陷；和（3）我们将根据中性粒细胞-胆管细胞相互作用的机制确定治疗靶点。这该项目有可能通过建立一个新的方法从根本上改变我们对酒精性肝炎的理解胆管细胞在这种疾病中的作用，并通过确定中性粒细胞如何与它们相互作用来引起胆汁淤积。我们对这种疾病分子发病机制理解的这种范式转变可能会进而确定新的治疗目标。考虑到目前尚无治疗酒精性肝炎的新疗法被证明可以自从 40 年前引入类固醇以来，这项工作就有潜力从根本上改变对患有这种危及生命的疾病的患者的治疗方法。