Novel Mechanisms of Hepatopulmonary Syndrome

在美国，肝硬化困扰着近300万人，并且由此产生的门静脉高压症的并发症是严重的。 是45-65岁人群的第四大死因。一个常见的并发症是 肝硬化综合征（HPS），当肺微血管扩张引起肺内 分流并损害动脉氧合。在接受肝移植评估的患者中，20%发生HPS (LT)无论肝脏疾病的严重程度如何，都显著增加了死亡率和患者的生活质量。 影响大约900，000美国人，HPS竞争对手的门静脉高压症的其他公认的后遗症 在发病率和临床影响方面。虽然LT可以解决HPS，但成本高，死亡率低。 移植后HPS增加。不幸的是，没有大规模的人类HPS研究。 为了满足这一需求，研究人员率先用实验动物研究HPS 以病人为中心的研究。我们在这两个病人身上都发现了异常的鞘脂信号 与HPS和实验动物模型，这可能与在肺部看到的血管生成。我们 也产生了初步的数据，表明较高水平的胆汁酸与 肺泡II型细胞凋亡、循环表面活性蛋白D水平升高和HPS。 本申请的总体目标是检查增加的1-磷酸鞘氨醇是否： 神经酰胺比率和循环胆汁酸与晚期肝病患者的HPS相关。我们 还将确定肝移植是否会降低SPD水平，与气体交换的变化成比例， HPS的解决方案。最后，我们将在HPS动物模型中研究这些新的机制， 胆汁酸和鞘氨醇激酶抑制。这是第一项针对HPS的大型多中心研究， 以确定这种知之甚少的肺血管疾病的机制和治疗靶点。

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.