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The acute respiratory distress syndrome with a mortality rate of up to 40% continues to be one of the central challenges of modern intensive care. Since the initial characterization of the Acute Respiratory Distress Syndrome (ARDS) in 1967 there have been no therapeutic approaches to lower morbidity and mortality in this lifethreatening disease until now. The pathophysiology of the ARDS extends to a therapy-resistant hypoxemia, a permeability pulmonary edema, reduced pulmonary compliance and frequently an associated pulmonary arterial hypertension (PAH). The level of the PAH correlates with the severity of the lung damage.
Recently, recombinant angiotensin converting enzyme 2 (ACE2) was shown to protect mice from acute lung injury (ALI). This effect is attributed to reduced bioavailability of angiotensin II and attenuated activation of its receptor AT1. Since ACE2 metabolizes angiotensin II to Ang-(1-7), we hypothesized that this effect alternatively is mediated via activation of Ang-(1-7) receptor, the receptor MAS.
The oleic acid model exhibits many pathophysiological similarities with acute respiratory failure. Therefore, it was used as a stable and reproducible model of lung damage within the scope of the present thesis. Central venous injection of 0.2 g/kg body weight oleic acid induced a stable lung damage within a trial period of 240 min. This was characterized by a low- to medium-grade pulmonary hypertension, systemic hypotension and various specifically measured inflammatory parameters of the lung tissue such as, for example, pulmonary edema and protein extravasation. In this model we investigated the effects of intravenously infused Ang-(1-7) in three experimental models and probed for the role of Ang-(1-7) and AT1 receptors in the protection from acute lung failure. Continuous infusion of Ang-(1-7) respectivly AVE0991 starting 30 min after administration of oleic acid, protected rats from ALI. This was evident by reduced lung edema, protein extravasation, myeloperoxidase activity which was an indication for the accumulation of neutrophiles granulocytes. The blood pressure drop due to the oleic acid infusion normalizes again in the course of the trial, and an increase of the pulmonary-vascular resistance as characteristic for the acute phase of the lung damage is also prevented. These findings identify the administration of Ang-(1-7) and AVE0991 as a promising new therapy approach to treat the ARDS due to their beneficial effect transmitted via Ang-(1-7) receptors in the experimental acute respiratory distress. To analyze the signal transduction of this mechanism more precisely, the role of Ang-(1-7) receptors was tested employing the antagonists A779 and D-Pro7-Ang-(1-7). These receptor antagonists have different action profiles and inhibit Ang-(1-7) receptors in different ways, one of which may possibly be the receptor MAS. This occurred both with sole administration
of the respective antagonists and in combination with exogenously supplied Ang-(1–7). Furthermore, it has been verified whether a reduction of the lung damage will also take place via ACE2 effects and the breakdown of AngII as well as reduced stimulation of AT1. For this purpose, trials were conducted with the AT1 receptor antagonist Irbesartan. The results regarding Irbesartan also indicate that the beneficial effects of a pharmacological blocking of the AT1 receptor, are, at least in part, mediated via an increased formation of Ang-(1-7) receptors. Both Ang-(1-7) antagonists blocked the protective effect of Irbesartan on blood pressure and led to an increased pulmonary-vascular resistance. The difference in the blockade was that A779 could not attenuate the acivity of the myeloperoxidase and D-Pro7-Ang-(1-7) blocked the stabilisation of the vascular barrier. Therefore the administration of these antagonists again led to a deterioration of the OA-mediated lung damage. These data first demonstrate the effects of Ang-(1-7) and its non-peptidic analogue AVE0991 in the oleic acid induced lung injury model. These findings can be taken as a basis for a new promising therapeutic strategy for the treatment of ALI.