The Paracrine Regulation of Mast Cells During Biliary/Cholangiocyte Repair and Damage

描述（由申请人提供）：胆管病（原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC））的特征是胆管细胞的增殖/损失，胆管细胞是胆上皮细胞。在胆汁淤积期间，胆汁增生/损伤是由自分泌/旁分泌机制调节的。例如，在增生性胆管细胞增殖过程中，胆管体积增加，增殖的胆管细胞释放出许多因子，如组胺，可能是为了维持胆管体积的增加。在胆管减少状态下，胆管体积减少，胆管细胞受损，无法维持胆道稳态。研究结果表明：(1)胆管细胞表达组胺受体（HRs）和组氨酸脱羧酶（HDC），组氨酸脱羧酶是调节组胺合成的关键酶；（ii）胆管细胞释放组胺；（iii）抑制胆汁HDC通过自分泌途径降低增生性和肿瘤性胆管细胞的生长和血管内皮生长因子（VEGF）。除了对胆管细胞增殖/损失的自分泌调节外，还必须考虑邻近肝细胞对胆道功能的旁分泌调节。已证实PBC和PSC患者的血浆组胺水平较高，胆管附近的肝肥大细胞数量增加。当被激活时，肝肥大细胞释放许多因子，如组胺到微环境中，我们认为这些因子影响胆管病变中胆管细胞的增殖/凋亡反应。在我们的提案中，我们提供的初步数据支持以下假设：肥大细胞在损伤后通过c-kit/SCF相互作用浸润肝脏，肥大细胞通过与H1和H2 hr和特异性microrna相互作用改变肝损伤或修复模型中大小胆管细胞的增殖反应。我们提出的研究具有创新性，可能会提供重要的临床相关数据，以增加对胆道疾病调节的理解，并为新的治疗策略提供见解。

DESCRIPTION (provided by applicant): Cholangiopathies (Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC)) are characterized by the proliferation/loss of cholangiocytes, which are the cells that line the biliary epithelium. During cholestasis, biliary hyperplasia/damage is regulated by both autocrine/paracrine mechanisms. For example, during hyperplastic cholangiocyte proliferation bile duct mass increases and proliferating cholangiocytes release numerous factors like histamine presumably to sustain the increased bile duct mass. In ductopenic states, bile duct mass decreases and cholangiocytes are damaged and unable to maintain biliary homeostasis. We have shown that: (i) cholangiocytes express histamine receptors (HRs) and histidine decarboxylase (HDC), the key enzyme regulating histamine synthesis; (ii) cholangiocytes release histamine; and (iii) inhibition of biliry HDC decreases both hyperplastic and neoplastic cholangiocyte growth and vascular endothelial growth factor (VEGF) by autocrine pathways. Besides the autocrine regulation of cholangiocyte proliferation/loss, paracrine regulation of biliary function by neighboring hepatic cells must be considered. It has been demonstrated in patients with PBC and PSC that histamine plasma levels are higher and that there are increased numbers of hepatic mast cells in the proximity of bile ducts. When activated, hepatic mast cells release numerous factors like histamine into the microenvironment, which we propose influence cholangiocyte proliferative/apoptotic responses in cholangiopathies. In our proposal, we present preliminary data supporting the hypothesis that mast cells infiltrate the liver following damage via c-kit/SCF interaction and that mast cells alte the proliferative response of small and large cholangiocytes in models of liver damage or repair by interaction with H1 and H2 HRs and specific microRNAs. Our proposed studies are innovative and will likely provide important, clinically relevant data to add to the understanding f the regulation of biliary disorders and also offer insight into novel treatment strategies.