Interactions between neutrophils and cholangiocytes in alcoholic hepatitis

项目概要/摘要 酒精性肝炎是酒精性肝病的严重并发症，可能危及生命， 短期死亡率高达20- 50%。传统上，酒精性肝炎被认为主要是由于 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，并且胆汁淤积恶化实际上与更差的预后相关。这是一个重要 概念，因为胆汁淤积通常是一个独立的过程，从肝细胞损伤，所以它的存在， 可能提示以前未被认识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 胆管上皮细胞或胆管细胞。许多肝脏疾病很大程度上或完全是由于胆管细胞 损伤或功能障碍，并且这些胆管病的特征在于胆汁淤积。尽管他们的广泛 不同的病因，胆管细胞3型三磷酸肌醇受体（ITPR 3）表达的缺失， 这是导致胆汁淤积的胆管病中的最后一个共同途径。ITPR 3发挥着重要作用 作用，因为它是胆管细胞中主要的细胞内钙释放通道，并且其表达是 调节胆汁液和碳酸氢盐分泌所必需的。这个项目将调查的想法， 胆管细胞参与发生在酒精性肝炎中的胆汁淤积， 胆管病，这也是由于ITPR 3的丢失。特别是，该项目将测试假设， 酒精性肝炎中发生的胆汁淤积性变化部分是由于 胆管细胞和嗜中性粒细胞。此外，胆管细胞和肝细胞的相对贡献， 将确定胆汁淤积。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 确定酒精性肝炎中胆管细胞是否以及为什么具有内在分泌缺陷;以及（3） 我们将根据嗜中性粒细胞-胆管细胞相互作用的机制确定治疗靶点。这 该项目有可能从根本上改变我们对酒精性肝炎的理解，通过建立一个新的 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， 胆汁淤积我们对这种疾病的分子发病机制的理解的这种范式转变可能会在 从而为治疗确定新的目标。考虑到没有新的治疗酒精性肝炎的方法已被证明， 自从40年前开始使用类固醇以来，这项工作有可能 从根本上改变对这种危及生命的疾病患者的治疗方法。

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.