Prevention of the secondary cerebral organ damage by stimulation of the AT2-receptor and the receptor Mas in a model of acute lung injury

本项目评估直接刺激AT2受体和受体Mas对急性肺损伤模型中继发性脑器官损伤的治疗潜力。本项目的主要目的是证明特异性激动剂Compound 21 （C21）和AVE0991对这两种受体的药理激活可能是一种成功的治疗策略，一方面可以治疗急性肺损伤，另一方面可以预防继发性脑器官损伤。项目重点是肺和脑炎症的表征，器官损伤的量化以及细胞凋亡和自噬等细胞死亡和生存机制的评估。此外，该项目旨在描述，至少部分，通过下调erk级联的潜在信号通路。一个遥远的目标，也是这个项目的愿景是描述一个新的，潜在的有益的治疗策略，患者急性呼吸窘迫综合征。到目前为止，还没有特定的药物干预措施可以改善这些患者的预后或减轻继发性器官损伤。从临床角度来看，对这些危重患者采取新的干预策略是值得的。在这方面，本项目包括对本课题的基础研究。如果实验结果为阳性，则可以开展临床研究来评估AT2/受体Mas在急性肺衰竭患者中的激活原理。

This project evaluates the therapeutic potential of a direct stimulation of the AT2 receptor and the receptor Mas on the secondary cerebral organ damage in a model of acute lung injury. Main goal of this project is to demonstrate that pharmacological activation of these two receptors using the specific agonists Compound 21 (C21) and AVE0991 might be a successful, therapeutic strategy in treatment of the acute lung injury on the one hand, and also in prevention of the secondary cerebral organ damage on the other hand. Focus of the project is the characterization of the pulmonary and cerebral inflammation, the quantification of the organ damage and the evaluation of cellular mechanisms involved in cell death and survival such as apoptosis and autophagy. Also, the project aims to describe, at least in part, the underlying signaling pathways via a down-regulation of the ERK-cascade. A distant goal and also the vision of this project is to describe a new, potentially beneficial treatment strategy for patients with acute respiratory distress syndrome. To date, there are no specific pharmacological interventions available to improve outcomes or to attenuate secondary organ damages in these patients. From the clinical perspective, a new intervention strategy for these critically-ill patients would be worthwhile. In this respect, the project comprises fundamental research to this topic. Positive experimental results given, clinical studies could be conducted to evaluate the principle of a AT2/receptor Mas activation in patients with acute lung failure.