This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic Iiver disease and its complications cause significant morbidity and mortality and rank among the top ten causes of death in the United States. One unique complication is the hepatopulmonary syndrome (HPS) which is found in 8-15% of patients with cirrhosis and results when intrapulmonary microvascular dilatation results in hypoxemia. There are no effective medical therapies for HPS. Liver transplantation is the sole treatment option, although peri-operative mortality appears higher in patients with HPS than in patients without HPS, particularly when severe. Despite the prevalence of HPS and the UNOS policy of increasing priority for transplantation once moderate hypoxemia due to HPS is present, fundamental questions and a lack of prospective data remain regarding epidemiology, natural history, pathogenesis, therapy and the efficacy of transplantation. These questions and the unique nature of this disorder highlight the importance of developing a network of liver transplantation centers with specific experience and interest to study this syndrome. Experimental work in HPS models provides a rationale for exploring specific genetic polymorphisms as contributors to susceptibility and for defining whether pentoxifylline ameliorates gas exchange abnormalities. The broad goal of this project is to understand the epidemiology, natural history, and pathogenesis of HPS in order to maximize patient outcomes and develop effective therapies. To accomplish this goal, the following specific aims will be undertaken. In Aim 1, we will establish an alliance of academic centers with expertise in advanced liver disease, liver transplantation and pulmonary vascular disease to study HPS by a) developing an organizational infrastructure, b) defining diagnostic criteria and, c) standardizing evaluation and establishing clinical tissue and specimen acquisition. In Aim 2, we will use the alliance to investigate clinical outcomes, pathogenesis and therapy of HPS by a) initiating prospective evaluation, data and specimen collection and clinical follow up, b) defining if genetic polymorphisms in specific candidate genes are associated with susceptibility to HPS and c) designing and initiating an open label pilot trial of pentoxifylline in severe HPS. The data obtained from completion of these aims will be used to design and submit an RO-1 application by the HPS Investigative Group.