靶向异常通路的动脉性肺动脉高压新型药物研发

Development of novel therapies targeting at dysregulated signaling pathways in pulmonary arterial hypertension

动脉性肺动脉高压(pulmonary arterial hypertension,PAH)是以肺血管阻力和肺动脉压力升高为主要表现的肺血管疾病,肺小血管重塑是其重要病理改变,如不及时治疗可导致右心室衰竭,威胁生命。目前针对PAH的治疗选择有限,已上市药物的主要作用是扩张肺血管,虽能缓解症状,但对预后的改善效果不佳。近年来,对PAH发病机制的研究取得了多项突破,多种信号通路的异常对PAH的作用已被逐渐阐明,以这些通路中的关键成员为靶点,已有多种新型药物正在研发和开展临床试验。本综述将这些疾病相关的信号通路归纳为5类,讨论针对这些异常通路的药物研发最新进展,重点关注已进入Ⅱ期临床试验阶段的新药物,探讨其作用机制及疗效,以期为今后PAH的新药研发提供参考。

Pulmonary arterial hypertension(PAH)is a complex pulmonary vascular disease characterized by progressive elevation of mean pulmonary artery pressure resulted from the pathological feature of pulmonary vascular remodeling.Without medical intervention,PAH can eventually lead to right heart failure and death of patients.Up to the present,there are few treatment options for PAH are still mainly function through pulmonary vasodilation.Although these treatments can alleviate symptoms,the prognosis remains poor.In recent years,breakthroughs have been made in understanding the pathogenesis of PAH,thus support the development of new treatment strategies targeting at dysregulation of signaling pathways in PAH.This review focuses on five critical pathways and the relevant drugs those entered phaseⅡclinical trials and discusses their therapeutic potential,so to provide a basis for future research on targeting therapies for PAH patients.