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

该项目评估了直接刺激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用特异性激动剂化合物21(C21)和AVE0991激活这两种受体可能是一种成功的治疗策略，一方面可以治疗急性肺损伤，另一方面也可以预防继发性脑器官损伤。该项目的重点是肺和脑炎症的特征，器官损伤的量化，以及与细胞死亡和生存有关的细胞机制的评估，如细胞凋亡和自噬。此外，该项目的目的是通过下调ERK级联信号转导通路，至少部分描述潜在的信号通路。这个项目的一个遥远的目标和愿景是描述一种新的、可能有益于急性呼吸窘迫综合征患者的治疗策略。到目前为止，还没有特定的药物干预措施可用于改善这些患者的预后或减轻继发性器官损害。从临床角度来看，为这些危重患者提供一种新的干预策略将是值得的。在这方面，该项目包含了对这一主题的基础研究。给出阳性实验结果，可以进行临床研究，以评估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.