Endothelial Cell Dysfunction in Pulmonary Arterial Hypertension

特发性（原发性）肺动脉高压（IPAH）是外源性肺动脉高压（PAH）的一个亚组，是一种罕见的疾病，发病率高，死亡率高。在IPAH或更广泛的PAH组中，没有常规筛查试验或有效的疾病活动性标志物。因此，患者通常出现在疾病的晚期。IPAH和其他形式PAH的发病机制尚不清楚。目前的想法主要集中在两种假说上：1)遗传易感性，2)触发刺激引发肺血管损伤，导致内皮细胞功能障碍。

Idiopathic (primary) pulmonary arterial hypertension (IPAH), a subgroup of plexogenic pulmonary arterial hypertension (PAH), is a rare disorder associated with severe morbidity and high mortality rates. There are no routine screening tests or validated markers of disease activity in IPAH, or the broader group of PAH. Therefore, patients usually present at advanced stages of disease. The pathogenesis of IPAH and other forms of PAH remain unclear. Current thinking focuses on a two-hit hypothesis: 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, resulting in endothelial cell dysfunction. Endothelial cells are normally shed into the circulation and are a valuable source of clinical material for studying diseases characterized by endothelial cell dysfunction. Unfortunately, no clear methodology exists for isolating clinically relevant numbers of circulating endothelial cells (CECs). In the bench phase of the project we plan to use flow cytometry to develop a methodology for isolating clinically relevant numbers of viable CECs. We hypothesize that CECs can be used to define a subset of differentially regulated biomarkers in IPAH and other forms of PAH that may lead to earlier diagnosis and better methods for measuring responses to therapy. We also hope to identify novel targets for future therapeutic interventions. In the clinical phase of the project, we will recruit the following subject groups: 1) patients with IPAH and other forms of PAH (vascular injury-induced pulmonary hypertension) who currently are on no therapy, less than or equal to 6 months of IV therapy, or less than or equal to one year of oral therapy 2) patients with pulmonary hypertension (PH) ascribed to a nonvascular injury process and 3) normal individuals (controls). All subjects will undergo right heart catheterization. CECs drawn peripherally and from the pulmonary artery catheter will be characterized for disease phenotype by cell surface markers and oligonucleotide microarrays. Total RNA for microarrays will be prepared from CECs by cell sorting and subjected to amplification. In addition peripheral blood mononuclear cells (PBMCs) will also be isolated. PBMCs will be studied in depth using high density oligonucleotide microarrays to more fully characterize their transcriptome. We plan to follow response to therapy by restudying the same parameters in patients with IPAH or PAH after therapeutic intervention. We started actively enrolling into the pilot phase of the protocol in June 2006. We have enrolled 26 individuals to date.