Mediators of Pulmonary Vasodilatation in Liver Disease

描述（申请人提供）：肝肺综合征（HPS）是肝脏疾病的重要血管并发症，其中15-30%的肝硬化患者发生肺微血管扩张导致低氧血症。HPS的存在增加了死亡率，并且没有可用的药物治疗。胆总管结扎（CBDL）诱导的实验性胆汁性肝硬化再现了人HPS的肺血管和气体交换异常。当前周期表明，肝脏内皮素-1 （ET-1）的产生和释放以及内皮素- B （ETB）受体的肺表达增加是通过eNOS衍生的NO产生引发HPS的关键早期事件。肝前门静脉高压症患者肺ETB受体表达也增加，但肝脏ET-1的产生不增加，除非ET-1输注，否则不会发生HPS。增加的肺ETB受体水平与高动力循环的发展相关，反映了血管剪切应力的增加，这是已知的ETB受体表达的调节剂。由于ET-1和ETB受体在CBDL后发生改变，巨噬细胞也在肺血管中积聚，并通过产生血红素氧化酶-1衍生的一氧化碳，促进HPS在晚些时间点的进展。ET-1和ETB受体介导的效应是否招募和激活肺中的巨噬细胞尚不清楚。初步研究支持剪切应力和ET-1参与实验性HPS中肺ETB受体的过表达，并揭示选择性抑制ETB受体可降低肺微血管eNOS，抑制肺血管内巨噬细胞积聚，改善HPS。我们的假设是，在实验性HPS中，剪切应力/细胞因子诱导的肺血管内皮ETB受体过表达介导了内皮细胞和巨噬细胞ET-1的作用。我们将1)确定肝硬化和门脉高压中肺血管内皮ETB受体过表达的细胞机制和后果，2)测试ET-1和ETB受体介导的效应是否有助于肺血管内皮中单核细胞/巨噬细胞的粘附和激活，3)评估ETB受体改变在体内实验性HPS发病机制中的作用。

DESCRIPTION (provided by applicant): The hepatopulmonary syndrome (HPS) is an important vascular complication of liver disease where 15-30% of cirrhotic patients develop pulmonary microvascular dilatation causing hypoxemia. The presence of HPS increases mortality and no medical therapies are available. Experimental biliary cirrhosis induced by common bile duct ligation (CBDL) reproduces the pulmonary vascular and gas exchange abnormalities of human HPS. Current cycle shows that hepatic production and release of endothelin-1 (ET-1) and increased pulmonary expression of the endothelin B (ETB) receptor are critical early events that trigger HPS through eNOS derived NO production. Pulmonary ETB receptor expression is also increased in prehepatic portal hypertension but hepatic ET-1 production does not rise and HPS does not develop unless ET-1 is infused. Increased pulmonary ETB receptor levels correlate with the development of a hyperdynamic circulation reflecting increased vascular shear stress, a known modulator of ETB receptor expression. As ET-1 and ETB receptor alterations occur after CBDL, macrophages also accumulate in the pulmonary vasculature and we contributes to the progression of HPS at later time points, by producing heme oxygenase-1 derived carbon monoxide. Whether ET-1 and ETB receptor mediated effects recruit and activate macrophages in the lung is unknown. Preliminary studies support that shear stress and ET-1 contribute to pulmonary ETB receptor overexpression in experimental HPS and reveal that selective ETB receptor inhibition may decrease pulmonary microvascular eNOS, inhibit accumulation of pulmonary intravascular macrophage and improve HPS. Our hypothesis is that shear stress/cytokine induced pulmonary vascular endothelial ETB receptor overexpression mediates ET-1 effects in the endothelium and macrophages in experimental HPS. We will 1) define the cellular mechanisms and consequences of pulmonary vascular endothelial ETB receptor overexpression in cirrhosis and portal hypertension, 2) test if ET-1 and ETB receptor mediated effects contribute to adhesion and activation of monocytes/macrophages in the pulmonary vascular endothelium and 3) assess the role of ETB receptor alterations in the pathogenesis of experimental HPS in vivo.