Regulation of Pulmonary Vascular Tone During Cirrhosis

肝硬化期间肺血管张力的调节

• 批准号: 6527443
• 负责人: ETHAN P. CARTER
• 金额: $ 19.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527443
• 关键词: calcium channel; calcium flux; carbon monoxide; cell communication molecule; cellular pathology; cholanate compound; endothelin; gene expression; heme oxygenase; hypoxia; laboratory mouse; laboratory rat; liver cirrhosis; medical complication; nitric oxide; oxygen tension; pathologic process; potassium channel; pulmonary circulation; respiratory circulation disorder; respiratory hypoxia; vascular smooth muscle; vasoconstriction; vasodilation; vasomotion

The cellular mechanisms governing the regulation of pulmonary vascular tone are complex and incompletely understood, particularly during pathphysiological conditions. One such pathophysiological condition is hepatopulmonary 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 vasodilations in the absence of intrinsic cardiopulmonary disease. This syndrome occurs in 15 - 30 percent of cirrhotic individuals and vastly complicates their treatment. Nitric oxide (NO) has been postulated to be central to the development of hepatopulmonary syndrome. An animal model of hepatopulmonary syndrome recently has been developed in rats that has proven useful for investigating to pathogenesis of hepatopulmonary syndrome. These animals have intrapulmonary shunting and hypoxemia. The mechanisms linking NO to the development of hepatopulmonary syndrome 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 vasocontrictor endothelin (ET-1) is decreased in cirrhotic rats. Evidence is also provided showing that vascular smooth muscle potassium channels are activated during cirrhosis. These are the first data ever, providing a mechanism for the pulmonary vasodilation and blunted hypoxic pressor response during cirrhosis. Additional data is shown demonstrating that during cirrhosis the stress response gene heme oxygenase-1 (HO-1) is significantly upregulated in lung and liver and decreased in kidney. HO-1 enzymatic activity liberates CO, a known vasodilator that can act via cGMP-dependent and -independent pathways. Therefore, it is possible that the tissue-specific regulation of the HO-1/CO axis contributes to the pulmonary vasodilation and renal vasoconstriction during cirrhosis. Finally, to investigate the role of NO in alterations to ET-1, potassium channels, and HO-1, cirrhotic rats were chronically treated with a NO inhibitor. This treatment resulted in a complete reversal of the cirrhotic associated changes to gene expression. Taken together, our data suggest that during cirrhosis, NO is central to the development of hepatopulmonary syndrome acting not only as a vasodilator but also as a regulator of gene expression of ET-1, potassium channels, and HO-1. We will test the hypotheses that: (1) chronic NO elevation during cirrhosis renders the pulmonary circulation unresponsive to hypoxia via direct vasodilatory actions and indirect modifications to gene expression; (2) factors released by the cirrhotic liver regulate pulmonary vascular tone; (3) HO-1 derived CO contributes to the pulmonary vasodilation during cirrhosis. 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.

控制肺血管张力调节的细胞机制是复杂的且不完全理解的，特别是在病理生理条件下。 一种这样的病理生理状况是肝病综合征。肝病综合征是一种临床三联征，包括晚期肝病（通常为肝硬化）、导致严重全身性动脉低氧血症的肺气体交换异常（即分流）以及在无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 - 30%的阿尔茨海默病患者中，并使他们的治疗变得非常复杂。 一氧化氮（NO）被认为是肝病综合征发生的中心环节。 近年来，在大鼠中建立了一种肝硬变综合征动物模型，为肝硬变综合征发病机制的研究提供了一种新的动物模型。 这些动物存在肺内分流和低氧血症。 NO与肝病综合征发生的关系机制尚未明确。本研究采用体内和体外实验策略的综合方法，探讨了肝病综合征的潜在机制。 我们提供的初步数据表明，除了升高的NO和eNOS，在肺血管收缩内皮素（ET-1）的表达减少在哮喘大鼠。 还提供了证据，表明血管平滑肌钾通道在肝硬化期间被激活。 这是有史以来的第一个数据，提供了肝硬化时肺血管舒张和低氧加压反应减弱的机制。 另外的数据表明，在肝硬化期间，应激反应基因血红素加氧酶-1（HO-1）在肺和肝中显著上调，而在肾中降低。 HO-1酶活性释放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发挥作用。 因此，HO-1/CO轴的组织特异性调节可能有助于肝硬化期间的肺血管舒张和肾血管收缩。 最后，为了研究NO在ET-1、钾通道和HO-1改变中的作用，用NO抑制剂长期治疗糖尿病大鼠。 这种治疗导致了与基因表达相关的阿尔茨海默病变化的完全逆转。 两者合计，我们的数据表明，在肝硬化，NO是中央的发展肝硬化综合征不仅作为一种血管扩张剂，但也作为一个调节因子的基因表达的ET-1，钾通道，HO-1。 我们将检验以下假设：（1）肝硬化期间慢性NO升高通过直接的血管舒张作用和基因表达的间接修饰使肺循环对缺氧无反应;（2）肝硬化肝脏释放的因子调节肺血管张力;（3）HO-1衍生的CO有助于肝硬化期间的肺血管舒张。 这个项目不仅将确定肝病综合征的细胞基础，而且还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。