Cellular mode of action and spectrum of application of angiotensin-(1-7) for the treatment of acute lung injury and systemic inflammatory diseases

急性呼吸窘迫综合征（Acute respiratory distress syndrome， ARDS）是一种严重的急性肺损伤，以全身性肺部炎症、通透性肺水肿和肺气体交换受损为特征。在西方文明国家，ARDS每年导致的死亡人数是乳腺癌或前列腺癌的两倍。尽管对新的药物治疗策略进行了大量的多中心试验，但迄今为止，没有一种经过测试的干预措施能够成功地降低死亡率。血管紧张素(Ang)-(1-7)是Ang II的代谢物，通常与其负面作用相反。在第一个资助期内，申请人可以证明Ang-(1-7)的治疗应用几乎完全预防了急性肺损伤的所有典型特征，并且涉及一种或多种具有不同药理特征的受体。他们还得出了与急性肺损伤中Ang-(1-7)治疗的最佳时间窗有关的相关结果，并首次提示了有益作用的机制。在这些发现的基础上，申请人的目标是进行一系列实验来揭示Ang-(1-7)减轻肺损伤的机制。具体而言，将研究最初由申请人确定的Ang-(1-7)受体Mas的作用，以及三种血管受体（AT1a， AT1b和/或AT2）和其他候选受体对七肽保护作用的可能参与。此外，将确定由Ang-(1-7)刺激的信号通路以及负责保护作用的效应细胞。申请人进一步打算探索Ang-(1-7)的保护反应是否同样存在于全身性炎症性疾病中。该申请旨在建立Ang-(1-7)作为急性肺损伤和全身炎症性疾病的新治疗选择。预定的实验应确定这种保护的机制，并为快速转化方法搭建桥梁。这不仅将为Ang-(1-7)的临床应用提供更广泛的机制基础，而且还将为炎性肺和全身性疾病的创新干预提供更广泛的信息。因此，该项目可能不仅为患者个人，而且为整个社会经济系统创造重大利益。

Acute respiratory distress syndrome (ARDS) is a severe acute lung injury that is characterized by generalized pulmonary inflammation, lung edema of the permeability type, and impaired pulmonary gas exchange. In countries of the western civilization, ARDS causes about twice as many deaths per year as breast cancer or prostate cancer. Despite numerous multicenter trials for new pharmacological treatment strategies, none of the tested interventions could thus far succeed to lower mortality.Angiotensin (Ang)-(1-7) is a metabolite of Ang II and often opposes its negative effects. Within a first funding period, the applicants could show that the therapeutic application of Ang-(1-7) almost completely prevented all typical characteristics of acute lung injury and that one or more receptors with different pharmacological profile are involved. They also generated relevant results related to an optimal time window for the Ang-(1-7) therapy in acute lung injury and first hints for the mechanisms the beneficial effects are based on. Building on these findings, the applicants aim to perform a series of experiments to unmask the mechanisms by which Ang-(1-7) alleviates lung injury. Specifically, the role of the Ang-(1-7) receptor Mas, originally identified by the applicants, will be investigated as well as the possible involvement of the three AngII-receptors (AT1a, AT1b and/or AT2) and other candidate receptors for the protective effects of the heptapeptide. Furthermore, the signaling pathways stimulated by Ang-(1-7) will be identified as well as the effector cells responsible for the protective effect. The applicants further intend to explore whether the protective response of Ang-(1-7) is similarly present in systemic inflammatory diseases. The application aims to establish Ang-(1-7) as a new therapeutic treatment option for acute lung injury and systemic inflammatory diseases. The scheduled experiments shall identify the mechanisms underlying such protection and build the bridge for a rapid translational approach. This will not only provide a broader mechanistic basis for the intended clinical application of Ang-(1-7), but also generate more generalized information for innovative interventions in inflammatory lung as well as systemic diseases. Thus, the project might not only create a significant benefit for the individual patient but also for the whole socio-economic system.