Mediators of Pulmonary Vasodilatation in Liver Disease

描述（由申请人提供）：肝病综合征（HPS）是肝病的一种重要血管并发症，其中15-20%的肝病患者发生肺微血管扩张，导致低氧血症。HPS的存在显著增加死亡率，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IPS的肺血管和气体交换异常。目前的研究表明，内皮素-1（ET-1）从肝脏的产生和释放以及肺血管内皮中内皮素B（ET B）受体表达的增加是通过eNOS衍生的NO产生触发HPS的关键早期事件。肺内皮ETB受体的表达也增加了肝前性门静脉高压症，但肝ET-1的生产并没有上升，HPS不会发展，除非ET-1输注。肺ETB受体水平的增加与反映血管剪切应力增加的高动力循环的发展相关，血管剪切应力是ETB受体表达的已知调节剂。由于ET-1和ETB受体在CBDL后发生改变，巨噬细胞也在肺血管系统中积聚，我们发现它们通过产生血红素加氧酶-1衍生的一氧化碳在稍后的时间点促进HPS的进展。ET-1和ETB受体介导的效应是否也在肺中巨噬细胞的募集和活化中起作用尚不清楚。初步研究表明，切应力和ET-1参与了实验性HPS肺ETB受体的过度表达，并揭示选择性ETB受体抑制可减少肺微血管eNOS，抑制肺血管内巨噬细胞积聚，改善HPS。基于这些发现，我们的假设是，剪切应力/细胞因子诱导的肺血管内皮ETB受体过表达介导ET-1的影响，在内皮细胞和巨噬细胞在实验性HPS的发病和进展。为了检验这一假设，我们将1）定义肝硬化和门静脉高压中肺血管内皮ETB受体过表达的细胞机制和后果，2）检验ET-1和ETB受体介导的作用有助于肺血管内皮中单核细胞/巨噬细胞的粘附和活化的假设，和3）评估ETB受体改变在体内实验性HPS发病机制中的作用。我们的长期目标是利用对HPS血管功能障碍的理解来开发药物治疗，并作为理解其他肝脏血管并发症发病机制的范例。

DESCRIPTION (provided by applicant): The hepatopulmonary syndrome (HPS) is an important vascular complication of liver disease where 15-20% of cirrhotic patients develop pulmonary microvascular dilatation leading to hypoxemia. The presence of HPS significantly 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 -IPS. Work in the current cycle has shown that production and release of endothelin-1 (ET-1) from the liver and increased expression of the endothelin B (ETB) receptor in the pulmonary vascular endothelium are critical early events that trigger HPS through eNOS derived NO production. Pulmonary endothelial 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. The increase in pulmonary ETB receptor levels correlates 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 have found that they contribute 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 also play a role in the recruitment and activation of 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. Based on these findings, our hypothesis is that shear stress/cytokine induced pulmonary vascular endothelial ETB receptor overexpression mediates ET-1 effects in the endothelium and macrophages during the onset and progression of experimental HPS. To test this hypothesis we will 1) define the cellular mechanisms and consequences of pulmonary vascular endothelial ETB receptor overexpression in cirrhosis and portal hypertension, 2) test the hypothesis that 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. Our long-term goal is to use an understanding of vascular dysfunction in HPS to develop medical therapies and as a paradigm for understanding the pathogenesis of other vascular complications of liver.