Novel Mechanisms of Hepatopulmonary Syndrome

在美国，近300万人患有肝硬变，由此导致的门静脉高压症并发症有 年龄在45-65岁之间的人的第四大死因。一个常见的并发症是 肝肺综合征(HPS)，当肺微血管扩张导致肺内 分流和损害动脉的氧合。在接受肝移植评估的患者中，20%会发生HPS (Lt)，无论肝病的严重程度如何，并显著增加死亡率和恶化生活质量。 影响大约90万美国人的HPS与其他公认的门静脉高压症后遗症相媲美 在发病率和临床影响方面。虽然肝移植可以解决HPS，但成本高，死亡率高 HPS移植后增加。不幸的是，目前还没有关于HPS的大型人体研究。 为了满足这种需要，研究人员率先用实验动物进行了HPS的研究 通过以病人为中心的研究。我们在两位患者身上都发现了神经鞘脂信号的异常。 HPS和实验动物模型，这可能与在肺部看到的血管生成有关。我们 还产生了初步数据表明，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，以及HPS。 本申请的总体目标是检查增加的鞘氨醇1磷酸： 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按比例降低Spd水平与气体交换和 HPS的分辨率。最后，我们将在HPS动物模型中通过给药来研究这些新的机制。 胆汁酸和鞘氨醇激酶抑制。HPS的第一个大型多中心研究的主要影响将是 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.