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

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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.