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.