Leukotriene B4-mediated Pulmonary Arterial Hypertension

描述（由申请人提供）：肺动脉高压（PH）是一种常见的致命疾病，目前尚无已知的治疗方法。目前的治疗主要针对血管舒张，但对于一部分患者，肺部炎症也可能是致病因素。来自患有严重PH的动物和患者的肺表现出血管周围CD 68+巨噬细胞增加;当从患有PH的大鼠的肺中取出这些细胞时，在培养物中诱导肺动脉内皮细胞（PAEC）凋亡。这些肺巨噬细胞分泌的白三烯B4（LTB 4）似乎是该动物模型中血管损伤的关键介质。LTB 4还在体外产生抗肺动脉硬化的内皮细胞，同时促进肺动脉平滑肌细胞（PASMC）和成纤维细胞生长。LTB 4在大鼠和PH患者的肺和血液中升高，拮抗LTB 4可逆转严重的实验性PH。这些累积的研究结果表明，LTB 4拮抗作用有望成为患有这种致命疾病的患者的新的治疗方法。这项研究计划阐明巨噬细胞来源的LTB 4如何特异性地影响肺小动脉的三个血管层（PAEC，PASMC，外膜成纤维细胞）以及LTB 4产生与PH临床表现之间的相关性。该提案的一般假设是，在PH的演变过程中，巨噬细胞来源的LTB 4通过抑制关键存活信号杀死健康的天然PAEC，同时还促进存活的、表型改变的EC中的细胞凋亡抗性，LTB 4通过组织特异性BLT 1信号通路促进PASMC和成纤维细胞的增殖。具体目的1是确定巨噬细胞来源的LTB 4如何通过其对骨形态发生蛋白受体2（BMPR 2）和内皮一氧化氮合酶（eNOS）存活信号传导的影响来介导PH相关的PAEC损伤。目的2是确定巨噬细胞来源的LTB 4是否产生具有分子干性特征的抗肺结核PAEC。目的3：探讨LTB 4在PASMC和成纤维细胞增殖中的作用。最后，目的4是确定PH患者的血浆LTB 4水平和肺LTB 4生物合成，并将这些发现与临床活动相关联。

DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is a frequently lethal condition with no known cure. Current therapies primarily target vasodilation, but for a subset of patients, pulmonary inflammation may also be a pathogenic factor. Lungs from animals and patients with severe PH exhibit increased perivascular CD68+ macrophages; these cells when removed from the lungs of rats with PH induce pulmonary artery endothelial cell (PAEC) apoptosis in culture. Leukotriene B4 (LTB4) secreted by these lung macrophages appears to be the key mediator responsible for vascular injury in this animal model. LTB4 also generates apoptosis-resistant endothelial cells in vitro while promoting pulmonary artery smooth muscle cell (PASMC) and fibroblast growth. LTB4 is elevated in the lungs and blood of rats and patients with PH, and antagonizing LTB4 reverses severe experimental PH. These cumulative findings suggest that LTB4 antagonism holds promise as a new adjunctive therapy for patients suffering this deadly disease. Studies proposed in this grant address how macrophage- derived LTB4 specifically affects the three blood vessel layers of pulmonary arterioles (PAECs, PASMCs, adventitial fibroblasts) as well as the correlation between LTB4 production and the clinical presentation of PH. The proposal's general hypothesis is that during the evolution of PH, macrophage-derived LTB4 kills healthy native PAECs by inhibiting key survival signals while also promoting apoptosis-resistance in surviving, phenotypically-altered ECs, and that LTB4 enhances the proliferation of PASMCs and fibroblasts via tissue- specific BLT1-signaling pathways. Specific Aim 1 is to determine how macrophage-derived LTB4 mediates PH- relevant PAEC injury through its impact on bone morphogenetic protein receptor 2 (BMPR2) and endothelial nitric oxide synthase (eNOS) survival signaling. Aim 2 is to determine whether macrophage-derived LTB4 generates apoptosis-resistant PAECs with molecular stemness signatures. Aim 3 is to determine the role of LTB4 in PASMC and fibroblast proliferation. Finally, Aim 4 is to determine plasma LTB4 levels and lung LTB4 biosynthesis in PH patients and correlate these findings with clinical activity.