Regulation of Vascular Tone During Cirrhosis

控制肺血管张力调节的细胞机制是复杂和不完全了解的，特别是在病理生理条件下。其中一种情况是肝肺综合征。肝肺综合征是一种临床三联症，包括晚期肝病(通常为肝硬变)、肺气体交换异常(如分流)导致严重的全身动脉低氧血症以及在没有内源性心肺疾病的情况下广泛的肺血管扩张。这种综合征发生在15%的肝硬变患者中，极大地使他们的治疗复杂化。一氧化氮(NO)被认为在肝肺综合征的发生发展中起中心作用。大鼠胆总管结扎术是近年来发展起来的一种用于研究肝肺综合征发病机制的动物模型。这些动物有肺内分流，而且是低氧血症。NO与肝肺发育相关的机制尚未明确。这项建议采用体内和体外实验策略的综合方法来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，肝硬变大鼠肺内血管收缩因子内皮素(ET-1)的表达减少。此外，应激反应基因，血红素加氧酶(HO-1)，在肝硬变大鼠的肺中显著上调。HO-1的酶活性释放一氧化碳(CO)，一氧化碳是一种已知的血管扩张剂，可通过cGMP依赖和非依赖途径发挥作用。我们的功能生理学证据表明，NO的慢性升高导致了肺血管的改变，超出了NO作为血管扩张剂的能力。我们将测试假设：1)在肝硬变期间慢性NO升高导致肺循环对低氧无反应，这种情况可以通过抑制NO的产生或在NOS基因敲除小鼠中被逆转；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；以及3)HO-1的诱导是由NO进一步促进肺血管扩张引起的。该项目不仅将确定肝肺综合征的细胞学基础，而且还将有助于我们在最基本的水平上了解肺血管张力是如何控制的。

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.