Novel alveolar mechanisms of hypoxemia in hepatopulmonary syndrome

项目摘要(&A) 超过450万美国人患有肝硬变和最常见的肝肺综合征(HPS) 肝硬变的肺部并发症，在高达30%的患者中发生，并显著增加死亡率。不是 有效的治疗方法的存在是由于我们对细胞机制的不完全理解。虽然从古典上讲 被认为是肺泡微血管重塑引起的低氧血症，低氧血症之间的相关性差， HPS的微血管改变程度和预后仍不清楚。要解决这一知识 GAP，我们在实验性的HPS中发现了肺泡本身的新的异常，以及限制性的 人类疾病中的呼吸缺陷和循环胆汁酸升高。我们的假设是 肝硬变患者循环胆汁酸水平，影响肺泡上皮2型细胞(AT2细胞)，导致受损 肺表面活性物质的产生和限制性呼吸机缺陷影响HPS的进展和结局。 为了阐明胆汁酸和AT2细胞在HPS中的作用，我们建议1)评估胆汁和AT2细胞之间的相关性 酸水平以及HPS的存在和严重程度2)决定了AT2细胞在HPS中的作用，3)决定了 胆汁酸抑制AT2细胞丢失的机制和后果。这项工作的完成将定义 HPS中AT2细胞功能障碍的机制和意义，寻找新的治疗靶点，形成 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.