Leukotriene B4-mediated Pulmonary Arterial Hypertension

白三烯 B4 介导的肺动脉高压

基本信息

批准号：
8799595
负责人：
Mark Robert Nicolls
金额：
$ 17.39万
依托单位：
PALO ALTO VETERANS INSTIT FOR RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8799595
关键词：
Address Affect Anabolism Animal Model Animals Apoptosis Apoptotic Arachidonate 5-Lipoxygenase Autoimmune Process Biological Markers Biology Blood Blood Vessels Cell Proliferation Cells Cessation of life Clinical Data Disease Down-Regulation Eicosanoids Endothelial Cells Evolution Exhibits Exposure to Fibroblasts Gene Transfer Grant Growth Health Immune In Vitro Inflammation Inflammatory Injury LTB4R gene Lesion Leukotriene B4 Leukotrienes Life Lung MAPK14 gene Mediating Mediator of activation protein Mining Molecular Outcome Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphorylation Plasma Process Production Proliferating Pulmonary Circulation Pulmonary Hypertension Pulmonary Inflammation Pulmonary artery structure Rattus Regulation Research Resistance Role SPHK1 enzyme Signal Pathway Signal Transduction Smooth Muscle Myocytes Stem cells Testing Therapeutic Intervention Tissues Trees Up-Regulation Vascular Diseases Vasodilation Virus Work anti-endothelial cell antibody arteriole bone morphogenetic protein receptors cell injury cell type human NOS3 protein injured killings macrophage mitogen-activated protein kinase p38 prevent pulmonary arterial hypertension pulmonary artery endothelial cell receptor stem stemness vascular inflammation

Address Affect Anabolism Animal Model Animals Apoptosis Apoptotic Arachidonate 5-Lipoxygenase Autoimmune Process Biological Markers Biology Blood Blood Vessels Cell Proliferation Cells Cessation of life Clinical Data Disease Down-Regulation Eicosanoids Endothelial Cells Evolution Exhibits Exposure to Fibroblasts Gene Transfer Grant Growth Health Immune In Vitro Inflammation Inflammatory Injury LTB4R gene Lesion Leukotriene B4 Leukotrienes Life Lung MAPK14 gene Mediating Mediator of activation protein Mining Molecular Outcome Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphorylation Plasma Process Production Proliferating Pulmonary Circulation Pulmonary Hypertension Pulmonary Inflammation Pulmonary artery structure Rattus Regulation Research Resistance Role SPHK1 enzyme Signal Pathway Signal Transduction Smooth Muscle Myocytes Stem cells Testing Therapeutic Intervention Tissues Trees Up-Regulation Vascular Diseases Vasodilation Virus Work anti-endothelial cell antibody arteriole bone morphogenetic protein receptors cell injury cell type human NOS3 protein injured killings macrophage mitogen-activated protein kinase p38 prevent pulmonary arterial hypertension pulmonary artery endothelial cell receptor stem stemness vascular inflammation

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项目摘要

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.

描述（由申请人提供）：肺动脉高压（pH）是经常致命的情况，没有已知的治愈方法。当前的疗法主要靶向血管舒张，但对于一部分患者，肺部炎症也可能是致病因素。来自动物和严重pH的患者的肺表现出血管周围CD68+巨噬细胞的增加。这些细胞从pH的大鼠肺中去除时会诱导培养物中肺动脉内皮细胞（PAEC）凋亡。这些肺巨噬细胞分泌的白三烯B4（LTB4）似乎是该动物模型中负责血管损伤的关键介质。 LTB4还会在体外产生抗凋亡的内皮细胞，同时促进肺动脉平滑肌细胞（PASMC）和成纤维细胞生长。 LTB4在大鼠和pH患者的肺和血液中升高，拮抗LTB4逆转严重的实验pH。这些累积发现表明，LTB4拮抗作用有望成为患有这种致命疾病的患者的一种新的辅助疗法。该赠款中提出的研究涉及巨噬细胞衍生的LTB4如何特异性影响肺动脉动脉的三个血管层（PAEC，PASMC，增生成纤维细胞）以及LTB4产生与pH的临床表现之间的相关性。该提议的一般假设是，在pH的演变中，巨噬细胞来源的LTB4通过抑制关键的生存信号来杀死健康的本地PAEC，同时还促进了在生存，表型改变的EC中的凋亡抗性，LTB4可通过PASMCS和Fibrobllaster parter parter-agry-tecim-facheral-facia-1-ltt parter-nister-facheral-facia-1-blt and-nister-facheral-facheral-facters-ecimnter-facie-1-blt and and。具体目的1是确定巨噬细胞来源的LTB4如何通过影响骨形态发生蛋白受体2（BMPR2）和内皮一氧化氮合酶（ENOS）生存信号来介导相关的PAEC损伤。 AIM 2是确定巨噬细胞来源的LTB4是否会产生具有分子干性特征的抗凋亡的PAEC。目标3是确定LTB4在PASMC和成纤维细胞增殖中的作用。最后，目标4是确定pH患者的血浆LTB4水平和肺LTB4生物合成，并将这些发现与临床活性相关联。