PENTOXIFYLLINE FOR CIRRHOTIC PATIENTS WITH HEPATOPULMONARY SYNDROME

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 慢性肝病及其并发症会导致严重的发病率和死亡率，在美国位列前十大死因之一。一种独特的并发症是肝肺综合征(HPS)，这种综合征在8-15%的肝硬变患者中出现，是肺内微血管扩张导致低氧血症的结果。目前尚无有效的治疗HPS的药物。肝移植是唯一的治疗选择，尽管HPS患者的围手术期死亡率似乎比非HPS患者更高，尤其是在严重的情况下。尽管HPS的流行以及联合国操作系统的政策，即一旦出现HFS引起的中度低氧血症，就增加移植的优先级，但关于流行病学、自然病史、发病机制、治疗和移植疗效的基本问题和前瞻性数据仍然缺乏。这些问题和这种疾病的独特性质突出了发展一个具有特殊经验和兴趣研究这种综合征的肝移植中心网络的重要性。在HPS模型中的实验工作为探索特定的基因多态作为易感性的贡献者和 确定己酮可可碱是否能改善气体交换异常。这个项目的主要目标是了解HPS的流行病学、自然病史和发病机制，以便最大限度地提高患者的预后并开发有效的治疗方法。为实现这一目标，将实现以下具体目标。在目标1中，我们将建立一个学术中心联盟，这些中心拥有先进的肝病、肝移植和 肺血管疾病通过a)建立组织基础设施，b)定义诊断标准，以及c)标准化评估和建立临床组织和标本采集来研究HPS。在目标2中，我们将利用该联盟通过a)启动前瞻性评估、数据和样本收集以及临床随访，b)确定特定候选基因的基因多态是否与HPS的易感性相关，以及c)设计和启动己酮可可碱在重度HPS中的开放标签先导试验，以调查HPS的临床结果、发病机制和治疗方法。从完成这些目标获得的数据将被用于设计和提交HPS调查小组的RO-1申请。

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 liver 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 HFS 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.