Novel Mechanisms of Hepatopulmonary Syndrome

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Cirrhosis afflicts nearly 3 million people in the US, and complications from resultant portal hypertension are the fourth leading cause of death in individuals age 45-65 years. One common complication is the hepatopulmonary syndrome (HPS) which results when lung microvascular dilations cause intrapulmonary shunting and impair arterial oxygenation. HPS occurs in 20% of patients evaluated for liver transplantation (LT), regardless of the severity of liver disease, and significantly increases mortality and worsens quality of life. Affecting approximately 900,000 Americans, HPS rivals other well-established sequelae of portal hypertension in terms of incidence and clinical impact. Although LT can resolve HPS, costs are high and mortality is increased post-transplantation in HPS. Unfortunately, there are no large human studies of HPS. To address this need, the investigators have spearheaded the study of HPS with an experimental animal model and through patient-oriented research. We have found abnormal sphingolipid signaling in both patients with HPS and the experimental animal model which may be linked to the angiogenesis seen in the lungs. We have also generated preliminary data suggesting that higher levels of bile acids are associated both with alveolar Type II cell apoptosis, increased circulating surfactant protein D levels, and HPS. The overall objective of this application is to examine whether increased sphingosine 1 phosphate : ceramide ratio and circulating bile acids are associated with HPS in patients with advanced liver disease. We will also determine if liver transplant reduces SPD levels in proportion to changes in gas exchange and resolution of HPS. Finally, we will study these novel mechanisms in the animal model of HPS by administering bile acids and sphingosine kinase inhibition. The major impact of this first large multicenter study in HPS will be to identify mechanisms and therapeutic targets of this poorly understood pulmonary vascular disease.