Spaczyńska Monika, Rocha Susana F, Oliver Eduardo
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain.
Centro de Investigaciones Biomédicas en Red Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, 28029, Spain.
ACS Pharmacol Transl Sci. 2020 Jul 1;3(4):598-612. doi: 10.1021/acsptsci.0c00048. eCollection 2020 Aug 14.
Pulmonary arterial hypertension is a rare and devastating disease characterized by an abnormal chronic increase in pulmonary arterial pressure above 20 mmHg at rest, with a poor prognosis if not treated. Currently, there is not a single fully effective therapy, even though a dozen of drugs have been developed in the last decades. Pulmonary arterial hypertension is a multifactorial disease, meaning that several molecular mechanisms are implicated in its pathology. The main molecular pathways regulating the pulmonary vasomotor tone-endothelin, nitric oxide, and prostacyclin-are the most biologically and therapeutically explored to date. However, drugs targeting these pathways have already found their limitations. In the last years, translational research and clinical trials have made a strong effort in suggesting and testing novel therapeutic strategies for this disease. These approaches involve targeting the main molecular pathways with novel drugs, drug repurposing for novel targets, and also using combinatorial therapies. In this review, we summarize current strategies and drugs targeting the endothelin, nitric oxide, and prostacyclin pathways, as well as, the emerging new drugs proposed to cope with vascular remodelling, metabolic switch, perivascular inflammation, epigenetic modifications, estrogen deregulation, serotonin, and other neurohumoral mechanisms characteristic of this disease. Nowadays, pulmonary arterial hypertension remains an incurable disease; however, the incoming new knowledge makes us believe that new promising therapies are coming to the clinical arena soon.
肺动脉高压是一种罕见且严重的疾病，其特征为静息时肺动脉压力异常慢性升高至20 mmHg以上，若不治疗，预后较差。目前，尚无一种完全有效的治疗方法，尽管在过去几十年中已研发出十几种药物。肺动脉高压是一种多因素疾病，这意味着其病理涉及多种分子机制。调节肺血管舒缩张力的主要分子途径——内皮素、一氧化氮和前列环素——是迄今为止在生物学和治疗方面研究最多的。然而，针对这些途径的药物已发现存在局限性。近年来，转化研究和临床试验在为该疾病提出和测试新的治疗策略方面做出了巨大努力。这些方法包括用新药靶向主要分子途径、将药物重新用于新靶点以及使用联合疗法。在本综述中，我们总结了目前针对内皮素、一氧化氮和前列环素途径的策略和药物，以及为应对该疾病特有的血管重塑、代谢转换、血管周围炎症、表观遗传修饰、雌激素失调、5-羟色胺和其他神经体液机制而提出的新兴新药。如今，肺动脉高压仍然是一种无法治愈的疾病；然而，新获得的知识让我们相信，很快就会有新的有前景的治疗方法进入临床领域。
