Role of the Renin-Angiotensin System in the Regulation of Biliary Proliferation

描述(申请人提供)：人类慢性淤胆性肝病(即胆管病)会引发胆管细胞的增殖和损伤，而胆管细胞是构成胆道器官的上皮细胞。这些胆管病会导致发病率和死亡率，也是肝移植的主要原因。在胆管疾病的发展过程中，胆管细胞的增殖是维持胆管质量和功能的关键。增殖的胆管细胞在肝病发病机制中起神经内分泌作用，分泌激素和神经肽并对其作出反应，这些激素和神经肽参与调节肝脏炎症和胆汁淤积性肝病相关的胆汁纤维化的自分泌和旁分泌途径。阐明胆管细胞对胆汁淤积的增殖反应的调控因素对于制定治疗胆汁淤积性肝病的策略至关重要。目前应用的总体目标是确定局部胆管细胞肾素-血管紧张素系统(RAS)在胆汁淤积期间维持胆管肿块中所起的作用。我们最近获得的新数据表明，在胆管结扎(BDL)诱导的肝外胆汁淤积过程中，胆管细胞表达局部RAS，长期应用血管紧张素II(Ang II)可促进正常大鼠胆管细胞的增殖，并促进胆管细胞的增殖。我们还获得了独特的体外初步数据，表明在肝外阻塞性疾病期间发生的机械应激通过机械激活血管紧张素1型受体(AT1)诱导胆管细胞增殖。基于初步发现，我们提出了新的中心假说，即RAS在调节胆管肿块中起关键作用。因此，胆汁淤积期的胆管细胞增殖是通过配体(Ang II)和机械应激依赖的AT1刺激导致ERK1/2 MAPK通路依赖的信号机制激活，从而通过应激激活的MAPKs、JNK1/2和p381的协同信号激活胆管细胞增殖和局部RAS。我们的工作将集中于三个特定的目标，旨在检验以下工作假说：(I)配体Ang II激活AT1在调控胆管细胞增殖中起关键作用；(Ii)机械应激诱导的AT1激活和局部RAS在调控胆管细胞增殖中发挥独特作用；以及(Iii)在活体肝病模型中，AT1和RAS的配体和机械激活在控制胆管细胞增殖中发挥关键调节作用。了解RAS调节胆汁淤积症的胆管细胞增殖反应的细胞内机制，将在制定治疗肝病(例如，肝硬变、PBC、PSC和其他导管生成性疾病)的治疗策略方面发挥重要作用。公共卫生相关性：该应用的健康相关性是缺乏对慢性淤胆性肝病的有效治疗，如原发性胆汁性肝硬化症(PBC)和原发性硬化性胆管炎(PSC)。慢性胆汁淤积性肝病会损害肝脏的胆管。我们研究的基本原理是，这些研究的成功完成最终有望提供对胆汁淤积性肝病进展的更多了解，并增加开发慢性肝病新治疗范例的机会。

DESCRIPTION (provided by applicant): Human chronic cholestatic liver diseases (i.e., cholangiopathies) trigger the proliferation and damage of cholangiocytes that are the epithelial cells that line the biliary apparatus. These cholangiopathies cause morbidity and mortality and are a major reason for liver transplantation. During the progression of cholangiopathies, proliferation of cholangiocytes is critical for the maintenance of biliary mass and function. Proliferating cholangiocytes serve as a neuroendocrine compartment during liver disease pathogenesis and secrete and respond to hormones and neuropeptides, which contribute to the autocrine and paracrine pathways that modulate liver inflammation and biliary fibrosis associated with cholestatic liver diseases. The elucidation of the factors regulating the proliferative responses of cholangiocytes to cholestasis is critical for the development of therapeutic strategies for the treatment of cholestatic liver diseases. The overall objective of the current application is to determine the role that the local cholangiocyte renin-angiotensin-system (RAS) plays in the maintenance of biliary mass during cholestasis. We have recently obtained novel data indicating that cholangiocytes express a local RAS and that chronic administration of angiotensin II (Ang II) increases the proliferation of normal rat cholangiocytes and enhances the proliferation of cholangiocytes during extrahepatic cholestasis induced by bile duct ligation (BDL). We have also obtained unique in vitro preliminary data demonstrating that mechanical stress, which occurs during extrahepatic obstructive disorders, induces cholangiocyte proliferation via mechanical activation of the angiotensin type 1 receptor (AT1). Based on preliminary findings, we propose the novel central hypothesis that the RAS plays a key role in regulating biliary mass. As such, cholangiocyte proliferation during cholestasis is stimulated via ligand (Ang II)- and mechanical stress-dependent stimulation of the AT1 resulting in the activation of ERK1/2 MAPK pathway-dependent signaling mechanisms triggering activation of cholangiocyte proliferation and the local RAS via coordinated signaling of stress activated MAPKs JNK1/2 and p381. Our proposed work will focus on three specific aims designed to test the following working hypotheses: (i) activation of AT1 by the ligand Ang II plays a key role in the modulation of cholangiocyte proliferation; (ii) mechanical stress-induced activation of AT1 and the local RAS plays an unique role in the modulation of cholangiocytes proliferation; and (iii) ligand and mechanical activation of AT1 and the RAS plays a key regulatory role for controlling the proliferation of cholangiocytes during in vivo models of liver disease. Knowledge of the intracellular mechanisms through which the RAS modulates cholangiocyte proliferative responses to cholestasis will play an important role in the development of therapeutic strategies for the treatment of liver diseases (e.g., cirrhosis, PBC, PSC, and other ductopenic diseases). PUBLIC HEALTH RELEVANCE: The health relatedness of this application is that effective treatments are lacking for chronic cholestatic liver diseases, such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Chronic cholestatic liver diseases cause damage to the bile ducts of the liver. The rationale for our research is that the successful completion of the studies can ultimately be expected to provide a greater understanding of cholestatic liver disease progression and increase opportunities for the development of novel treatment paradigms for chronic liver diseases.