MEDIATORS OF PULMONARY VASODILATATION IN LIVER DISEASE

内皮功能障碍是慢性肝病血管异常的基础，其特征在于内皮型一氧化氮合酶水平和活性的变化。 这些变化是如何发生的，以及为什么血管床会发生变化，目前还不完全清楚。 肝硬化综合征是肝脏疾病的一种重要血管并发症，其中15- 20%的肝硬化患者发生肺微血管扩张，导致低氧血症。 没有有效的治疗方法。 实验性胆汁性肝硬化再现了与肺微血管内皮细胞一氧化氮水平和活性增加相关的人类肝病综合征的肺血管和气体交换异常。 单独的肝前门脉高压不会引起肺血管或内皮型一氧化氮合酶的改变，这意味着肝损伤过程中释放的介质可能会触发肺内皮的改变。 肝和血浆内皮素-1水平升高，并与实验性胆汁性肝硬化肺内血管扩张的程度直接相关，初步研究表明，慢性低水平内皮素-1输注肝前门脉高压动物的结果在选择性肺微血管扩张。尽管经典上被认为是血管收缩剂，但循环内皮素-1刺激内皮细胞内皮一氧化氮合酶活性并可引起血管舒张。 我们的假设是，内皮素-1，释放到循环中的肝损伤，优先激活肺血管内皮一氧化氮合酶，并触发肺微血管扩张。 为了验证这一假设，我们的具体目标是：1）确定慢性内皮素-1输注对正常人肺内血管舒张和内皮型一氧化氮合酶表达和活性的影响，肝前门脉高压症和胆道梗阻动物体内2）评估外源性内皮素的作用，1对离体肺血管段和正常肺血管内皮细胞内皮型一氧化氮合酶表达和活性的影响，肝前性门脉高压和胆道梗阻动物; 3）直接测量外源性内皮素-1对正常、肝前性门脉高压和胆道梗阻动物肺微血管反应性的影响。 我们的长期目标是利用对肝病综合征中内皮功能障碍的理解来开发特定的药物治疗，并作为理解肝病其他血管并发症发病机制的范例。

Endothelial dysfunction underlies the vascular abnormalities of chronic liver disease and is characterized by changes in the levels and activity of endothelial nitric oxide synthase. How these changes occur and why there is variability in the vascular beds involved is incompletely characterized. The hepatopulmonary syndrome is one important vascular complication of liver disease where 15-20 percent of patients with cirrhosis develop pulmonary microvascular dilatation leading to hypoxemia. No effective medical therapies are available. Experimental biliary cirrhosis reproduces the pulmonary vascular and gas exchange abnormalities of human hepatopulmonary syndrome in association with an increase in pulmonary microvascular endothelial nitric oxide levels and activity. Pre-hepatic portal hypertension alone does not cause pulmonary vascular or endothelial nitric oxide synthase alterations, implying that mediators released during hepatic injury may trigger endothelial alterations in the lung. Hepatic and plasma endothelin-1 levels rise and correlate directly with the degree of intrapulmonary vasodilatation in experimental biliary cirrhosis and preliminary studies reveal that chronic low level endothelin-1 infusion in pre-hepatic portal hypertensive animals results in selective pulmonary microvascular dilatation. Although classically recognized as a vasoconstrictor, circulating endothelin-1 stimulates endothelial cell endothelial nitric oxide synthase activity and can cause vasodilatation. Our hypothesis is that endothelin-1, released into the circulation during liver injury, preferentially activates pulmonary vascular endothelial nitric oxide synthase and triggers pulmonary microvascular dilatation. To test this hypothesis our specific aims will 1) define the effects of chronic endothelin-1 infusion on the development of intrapulmonary vasodilatation and endothelial nitric oxide synthase expression and activity in normal, pre- hepatic portal hypertensive and biliary cirrhotic animals in vivo 2) assess the effects of exogenous emdothelin-1 on endothelial nitric oxide synthase expression and activity in isolated pulmonary vascular segments and endothelial cells from normal, pre-hepatic portal hypertensive and biliary cirrhotic animals and 3) directly measure the effects of exogenous endothelin-1 on pulmonary microvascular reactivity in normal, pre-hepatic portal hypertensive and biliary cirrhotic animals. Our long-term goal is to use an understanding of endothelial dysfunction in hepatopulmonary syndrome to develop specific medical therapies and as a paradigm for understanding the pathogenesis of other vascular complications of liver disease.