A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension
A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension
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DOI：
10.1038/s41467-019-13139-9
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发表时间：
2019-11-15
影响因子：
16.6
通讯作者：
Lawrie, Allan
中科院分区：
文献类型：
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作者：
Arnold, Nadine D.;Pickworth, Josephine A.;Lawrie, Allan
肺动脉高压（PAH）是一种罕见但致命的疾病。目前的治疗方法可以延长预期寿命，但对导致肺动脉高压的进行性肺血管重塑的影响有限。骨保护素（OPG）在特发性PAH患者的血清和病变中升高，是肺动脉平滑肌细胞（PASMC）的有丝分裂原和迁移刺激物。在此，我们报告了OPG刺激PASMCs的促增殖和迁移表型是通过Fas受体介导的，并且在早期和晚期治疗的多种啮齿动物模型中，用靶向OPG的人抗体治疗可以减弱与PAH相关的肺血管重塑。我们还证明，在标准治疗血管扩张剂治疗的情况下，抗OPG抗体方法的疗效是由肺血管重塑的减少介导的。用治疗性抗体靶向OPG是PAH的潜在治疗策略。
Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.