Prevention of the secondary cerebral organ damage by stimulation of the AT2-receptor and the receptor Mas in a model of acute lung injury
Final Report Abstract
Acute respiratory distress syndrome (ARDS) is a severe, life-threatening condition that affects not only the lungs but also other organs, particularly the brain, through complex inflammatory processes. To date, there is a lack of specific pharmacological therapies that could mitigate both pulmonary inflammation and secondary cerebral organ damage. The reninangiotensin system (RAS) plays a central role in the pathophysiology of ARDS and the underlying inflammatory response. Anti-inflammatory and tissue-protective effects are mediated via the AT2 receptor and the Mas receptor. Compound 21 (C21) and AVE 0991 are highly selective receptor agonists and Angiotensin(1-7) analogs, respectively. The goal of this project was to investigate the anti-inflammatory potential of these two substances—specifically, the pharmacological stimulation of the aforementioned RAS receptors—and their combination on pulmonary and cerebral inflammation, gas exchange, and subsequent organ damage. For this purpose, an experimental rat model was used, in which acute respiratory distress syndrome was induced through repeated pulmonary lavage. The main finding of the project was that both C21 and AVE 0991 significantly inhibited pulmonary inflammation. The combined application of both substances enhanced this effect and additionally led to an improvement in pulmonary gas exchange in the experimental setting: The arterial oxygen partial pressure (PaO2), as a measure of the severity of gas exchange impairment in ARDS, was increased, while the arterial carbon dioxide partial pressure (Pa- CO2) was reduced. Consequently, there was an improvement in the acid-base balance of the test animals. Pharmacological blockade of the target receptors using selective receptor antagonists like PD123319 and A779 abolished these effects, confirming receptor specificity. In the brain, as expected, an inflammation response induced by experimental ARDS was detected. Pro-inflammatory cytokines such as IL-1 and TNF-α were elevated. Direct stimulation of the AT2 receptor with C21 significantly reduced this potentially tissue-damaging inflammation, whereas stimulation of the Mas receptor with AVE 0991 did not show the same effect. The underlying reasons for this observation remain unclear. In summary, this project generated new evidence suggesting that the combined stimulation of the AT2 receptor and the Mas receptor could be a promising therapeutic approach to mitigate pulmonary inflammation in the treatment of ARDS. From a clinical perspective, an effective pharmacological treatment for patients with ARDS remains highly desirable. Whether the findings of this project can be translated to humans in clinical trials remains to be seen.
