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Grant

Novel Alveolar Mechanisms of Hypoxemia in Hepatopulmonary Syndrome

Sponsored by National Heart, Lung, and Blood Institute

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$762.8K Funding
5 People
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Abstract

Project Summary & AbstractCirrhosis afflicts more than 4.5 million Americans and hepatopulmonary syndrome (HPS) the most commonpulmonary complication of cirrhosis occurs in up to 30% of patients and significantly increases mortality. Noeffective therapies exist due to our incomplete understanding of cellular mechanisms. Although classicallyrecognized as alveolar microvascular remodeling causing hypoxemia the poor correlation between hypoxemiathe degree of microvascular changes and outcomes in HPS remain unexplained. To address this knowledgegap we have identified novel abnormalities in the alveolus itself in experimental HPS along with restrictiveventilatory defects and elevated circulating bile acids in human disease. Our hypothesis is that elevatedcirculating bile acid levels in cirrhosis affect alveolar epithelial type 2 cells (AT2 cells) leading to impairedsurfactant 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 bileacid levels and the presence and severity of HPS 2) define the role of AT2 cells in HPS and 3) determine themechanisms and consequences of bile acid medicated AT2 cell loss. Completion of this work will define themechanisms and significance of AT2 cell dysfunction in HPS identify novel therapeutic targets and form thefoundation for a broader understanding of how chronic liver disease influences lung function.

People