Regulation of Vascular Tone During Cirrhosis

肝硬化期间血管张力的调节

• 批准号: 6516787
• 负责人: ETHAN P. CARTER
• 金额: $ 9.5万
• 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: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516787
• 关键词: cellular pathology; chloride channels; endothelin; heme oxygenase; laboratory mouse; laboratory rat; liver cirrhosis; nitric oxide; potassium channel; pulmonary circulation; vascular smooth muscle; vasomotion

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.

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。其中一种情况是肝肺综合征。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）、导致严重全身动脉低氧血症的肺气体交换异常（即分流）和无内源性心肺疾病的广泛肺血管扩张。这种综合征发生在15%的阿尔茨海默病患者中，并使其治疗变得非常复杂。一氧化氮（NO）被认为是肝病综合征发生的中心环节。结扎大鼠胆总管是近年来发展起来的一种研究肝病综合征发病机制的动物模型。这些动物存在肺内分流，并出现低氧血症。NO与肝病发展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，在肺血管收缩剂内皮素（ET-1）的表达减少在哮喘大鼠。此外，应激反应基因，血红素加氧酶（HO-1），显着上调，在肺动脉高压大鼠。HO-1酶活性释放一氧化碳（CO），一种已知的血管扩张剂，可通过cGMP依赖性和非依赖性途径发挥作用。我们的功能生理学证据表明，慢性升高的NO导致改变肺血管超出NO的能力，作为血管扩张剂。我们将检验以下假设：1）肝硬化期间慢性NO升高使肺循环对缺氧无反应，并且这可以通过抑制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它们的收缩能力; 3）NO诱导HO-1表达，进一步促进肺血管舒张。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。