Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, Singapore 117600, Singapore.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 16 Medical Drive, Singapore 117600, Singapore; Immunology Program, Life Science Institute, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore; Singapore-HUJ Alliance for Research and Enterprise, National University of Singapore, 1 CREATE Way, Singapore 138602, Singapore.
Curr Opin Pharmacol. 2018 Jun;40:9-17. doi: 10.1016/j.coph.2017.12.002. Epub 2017 Dec 27.
The renin-angiotensin system (RAS) plays a major role in regulating electrolyte balance and blood pressure. RAS has also been implicated in the regulation of inflammation, proliferation and fibrosis in pulmonary diseases such as asthma, acute lung injury (ALI), chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension (PAH). Current therapeutics suffer from some drawbacks like steroid resistance, limited efficacies and side effects. Novel intervention is definitely needed to offer optimal therapeutic strategy and clinical outcome. This review compiles and analyses recent investigations targeting RAS for the treatment of inflammatory lung diseases. Inhibition of the upstream angiotensin (Ang) I/Ang II/angiotensin receptor type 1 (ATR) pathway and activation of the downstream angiotensin-converting enzyme 2 (ACE2)/Ang (1-7)/Mas receptor pathway are two feasible strategies demonstrating efficacies in various pulmonary disease models. More recent studies favor the development of targeting the downstream ACE2/Ang (1-7)/Mas receptor pathway, in which diminazene aceturate, an ACE2 activator, GSK2586881, a recombinant ACE2, and AV0991, a Mas receptor agonist, showed much potential for further development. As the pathogenesis of pulmonary diseases is so complex that RAS modulation may be used alone or in combination with existing drugs like corticosteroids, pirfenidone/nintedanib or endothelin receptor antagonists for different pulmonary diseases. Personalized medicine through genetic screening and phenotyping for angiotensinogen or ACE would aid treatment especially for non-responsive patients. This review serves to provide an update on the latest development in the field of RAS targeting for pulmonary diseases, and offer some insights into future direction.
肾素-血管紧张素系统（RAS）在调节电解质平衡和血压方面起着重要作用。RAS 也参与了哮喘、急性肺损伤（ALI）、慢性阻塞性肺疾病（COPD）、特发性肺纤维化（IPF）和肺动脉高压（PAH）等肺部疾病中炎症、增殖和纤维化的调节。目前的治疗方法存在一些缺点，如皮质类固醇耐药、疗效有限和副作用。肯定需要新的干预措施来提供最佳的治疗策略和临床结果。本综述汇集和分析了最近针对 RAS 治疗炎症性肺部疾病的研究。抑制上游血管紧张素（Ang）I/Ang II/血管紧张素受体 1（ATR）途径和激活下游血管紧张素转换酶 2（ACE2）/Ang（1-7）/Mas 受体途径是两种可行的策略，在各种肺部疾病模型中均显示出疗效。最近的研究更倾向于开发靶向下游 ACE2/Ang（1-7）/Mas 受体途径，其中二氮嗪乙酰脲，一种 ACE2 激活剂，GSK2586881，一种重组 ACE2，和 AV0991，一种 Mas 受体激动剂，显示出进一步开发的巨大潜力。由于肺部疾病的发病机制非常复杂，RAS 调节可能单独使用或与皮质类固醇、吡非尼酮/尼达尼布或内皮素受体拮抗剂等现有药物联合使用，用于不同的肺部疾病。通过对血管紧张素原或 ACE 进行基因筛选和表型分析的个体化医学将有助于治疗，特别是对无反应的患者。本综述旨在提供 RAS 靶向肺部疾病领域的最新进展，并为未来的方向提供一些见解。
