Recently, overexpression of angiotensin converting enzyme 2 [ACE2] has been shown to markedly attenuate acute lung injury [ALI] in mice (Nature 2005, 436:112–6). Since ACE2 metabolizes angiotensin II [AngII] to angiotensin-(1–7) [Ang-(1–7)], this protective effect has been attributed to reduced activation of the angiotensin receptor 1 [AT1] by AngII, and major efforts are since underway to transfer this strategy into the clinic. Yet, an alternative explanation of the role of ACE2 is that the ACE2 product Ang-(1–7) itself may confer partial protection in ALI. Here, we tested this hypothesis in an established model of oleic acid-induced ALI in rats (Intensive Care Med 2008, in press).

In anaesthetized and ventilated Sprague-Dawley rats, ALI was induced by intravenous infusion of 0.2 g/kg oleic acid [OA] over 30 minutes. After 30 min, continuous infusion of Ang-(1–7) (50 pMol l-1 kg-1 min-1), the non-peptidic Ang-(1–7) receptor agonist AVE0991 (500 pMol l-1 kg-1 min-1), the Ang-(1–7) antagonist A779 (100 pMol l-1 kg-1 min-1) or the AT1 blocker irbesartan (10 mg kg-1) was started. Animals were euthanized 4 h after OA infusion, and ALI was evaluated by measurements of lung wet/dry ratio [W/D], myeloperoxidase [MPO] activity, and protein concentration in the bronchoalveolar lavage fluid [BAL protein].

OA infusion resulted in systemic hypotension (mean arterial blood pressure [AP]: control 1016.2; OA 60.19.3* mmHg; n=8 each, *p<0.05 vs. control) and ALI (W/D: control 5.30.2; OA 7.10.7*; MPO: control 1.90.4; OA 4.80.5* U/g; protein: control 1.00.1; OA 3.30.6 mg/ml). Ang-(1–7) infusion 30 min after OA attenuated both effects (AP: 85.17.5# mmHg; W/D: 5.40.2#; MPO: 1.60.2# U/g; protein: 1.50.3 mg/ml; n=8, #p<0.05 vs. OA). Similar effects were obtained by infusion of AVE0991 in rats with OA-induced ALI. Coincidental infusion A779 attenuated the protective effect of Ang-(1–7) on AP (66.37.5* mmHg; n=8), lung MPO (5.71.0* U/g) and in part on W/D (6.10.2*) and protein (2.40.3* mg/ml).

Irbesartan attenuated OA-induced ALI (AP: 91.39.7# mmHg; W/D: 5.50.2#; MPO: 2.90.2# U/g; protein: 1.80.3# mg/ml; n=8), but pulmonary yet not systemic effects were attenuated by simultaneous infusion of A779 (AP: 90.011.5 mmHg; W/D: 6.20.4†; MPO: 3.50.4 U/g†; protein: 2.20.4 mg/ml; n=8, †p<0.05 vs. irbesartan) indicating that the protective effects of irbesartan are in part attributable to stimulation of the Ang-(1–7) metabolic pathway.

Our results identify a protective effect of Ang-(1–7) in acute lung injury which contributes relevantly to the therapeutic effects of AT1 blockers in this scenario. Stimulation of the Ang-(1–7) pathway may therefore present a novel and promising strategy for the prevention and/or treatment of ALI. Sponsored by DFG KU 1218/4-1.