Novel alveolar mechanisms of hypoxemia in hepatopulmonary syndrome

项目概要和摘要 肝硬化折磨着超过450万的美国人，最常见的是肝病综合征（HPS）。 肝硬化的肺部并发症，发生在高达30%的患者中，并显著增加死亡率。没有 由于我们对细胞机制的不完全理解，所以存在有效的疗法。虽然经典 公认为肺泡微血管重塑引起低氧血症，低氧血症之间的相关性差， HPS的微血管改变程度和结局仍无法解释。为了解决这个问题， 间隙，我们已经确定了新的异常，在肺泡本身的实验HPS，沿着与限制性 人类疾病中的消化缺陷和循环胆汁酸升高。我们的假设是 肝硬化时循环胆汁酸水平影响肺泡上皮2型细胞（AT 2细胞），导致受损 表面活性剂的产生和限制性澄清缺陷影响HPS的进展和结果。 为了阐明胆汁酸和AT 2细胞在HPS中的作用，我们建议1）评估胆汁与AT 2细胞之间的相关性 酸水平和HPS的存在和严重程度2）确定AT 2细胞在HPS中的作用，3）确定 胆汁酸介导的AT2细胞损失的机制和后果。这项工作的完成将确定 HPS中AT2细胞功能障碍的机制和意义，确定新的治疗靶点， 为更广泛地了解慢性肝病如何影响肺功能奠定了基础。

Project Summary & Abstract Cirrhosis afflicts more than 4.5 million Americans and hepatopulmonary syndrome (HPS), the most common pulmonary complication of cirrhosis, occurs in up to 30% of patients and significantly increases mortality. No effective therapies exist due to our incomplete understanding of cellular mechanisms. Although classically recognized as alveolar microvascular remodeling causing hypoxemia, the poor correlation between hypoxemia, the degree of microvascular changes, and outcomes in HPS remain unexplained. To address this knowledge gap, we have identified novel abnormalities in the alveolus itself in experimental HPS, along with restrictive ventilatory defects and elevated circulating bile acids in human disease. Our hypothesis is that elevated circulating bile acid levels in cirrhosis, affect alveolar epithelial type 2 cells (AT2 cells), leading to impaired surfactant production and restrictive ventilatory defects which influence the progression and outcome of HPS. To elucidate the role of bile acids and AT2 cells in HPS, we propose to 1) assess the correlation between bile acid levels and the presence and severity of HPS 2) define the role of AT2 cells in HPS and 3) determine the mechanisms and consequences of bile acid medicated AT2 cell loss. Completion of this work will define the mechanisms and significance of AT2 cell dysfunction in HPS, identify novel therapeutic targets and form the foundation for a broader understanding of how chronic liver disease influences lung function.