Regulation of Vascular Tone During Cirrhosis

调控肺血管张力的细胞机制是复杂和不完全理解的，特别是在病理生理条件下。其中一种情况是肝肺综合征。肝肺综合征是晚期肝病（通常为肝硬化）、肺气体交换异常（即分流）导致严重的全身动脉低氧血症以及在没有内在心肺疾病的情况下广泛的肺血管扩张的临床三联征。15%的肝硬化患者出现这种综合征，并使其治疗大大复杂化。一氧化氮（NO）被认为是肝肺综合征发展的核心。大鼠胆总管结扎是最近开发的一种动物模型，已被证明对研究肝肺综合征的发病机制有用。这些动物有肺内分流和低氧血症。一氧化氮与肝肺发展的机制尚未明确。本研究采用体内和体外实验的综合方法研究肝肺综合征的潜在机制。我们提供的初步数据表明，除了NO和eNOS升高外，肝硬化大鼠肺中血管收缩素（ET-1）的表达也下降。此外，应激反应基因血红素加氧酶（HO-1）在肝硬化大鼠肺中显著上调。HO-1酶活性释放一氧化碳（CO），一种已知的血管扩张剂，可以通过cgmp依赖性和非依赖性途径起作用。我们的功能生理学证据表明，一氧化氮的慢性升高导致肺血管的改变，超出了一氧化氮作为血管扩张剂的能力。我们将验证以下假设：1)肝硬化期间慢性NO升高使肺循环对缺氧无反应，这可以通过抑制NO产生或在nos敲除小鼠中逆转；2)慢性NO升高激活肺动脉血管平滑肌细胞K+和/或Cl-通道，使这些细胞超极化并降低其收缩能力；3) NO诱导HO-1进一步促进肺血管舒张。这个项目不仅将定义肝肺综合征的细胞基础，而且将有助于我们了解肺血管张力是如何在最基本的水平上控制的。

Cellular mechanisms governing the regulation of pulmonary vascular tone are complex and incompletely understood, particular during pathophysiological conditions. One such condition is hepatopulrnonary syndrome. Hepatopulmonary syndrome is a clinical triad of advanced liver disease (usually cirrhosis), pulmonary gas exchange abnormalities (i.e. shunting) leading to severe systemic arterial hypoxemia, and widespread pulmonary vascular dilatations in the absence of intrinsic cardiopulmonary disease. This syndrome occurs in 15% of cirrhotic individuals and vastly complicates their treatment. Nitric oxide (NO) has been postulated to be central to the development of hepatopulmonary syndrome. Ligation of the common bile duct in rats is a recently developed animal model that has proven useful for investigating the pathogenesis of hepatopulmonary syndrome. These animals have intrapulmonary shunting and are hypoxemic. The mechanisms linking NO to the development of hepatopulmonary have not been defined. This proposal investigates the underlying mechanisms of hepatopulmonary syndrome using a comprehensive approach of in vivo and in vitro experimental strategies. We provide preliminary data demonstrating that in addition to elevated NO and eNOS, expression in lung of the vasoconstrictor endothelin (ET-1) is decreased in cirrhotic rats. Also, the stress response gene, heme oxygenase (HO-1), is significantly upregulated in lungs of cirrhotic rats. HO-1 enzymatic activity liberates carbon monoxide (CO), a known vasodilator that can act via cGMP-dependent and -independent pathways. Our functional physiological evidence suggests that the chronic elevation of NO leads to alterations to the pulmonary vasculature beyond NO's ability to act as a vasodilator. We will test the hypotheses that: 1) Chronic NO elevation during cirrhosis renders the pulmonary circulation unresponsive to hypoxia and that this can be reversed by inhibiting NO production or in NOS-knockout mice; 2) Chronic NO elevation activates pulmonary artery vascular smooth muscle cell K+ and/or Cl- channels hyperpolarizing these cells and reducing their contractile ability; and 3) HO-1 induction is caused by NO further contributing to pulmonary vasodilation. This project will not only define the cellular basis for hepatopulmonary syndrome, but will also contribute to our understanding of how pulmonary vascular tone is controlled at the most basic level.