Angiotensin-(1-7) protects from experimental acute lung injury.
OBJECTIVE
Recently, recombinant angiotensin-converting enzyme 2 was shown to protect mice from acute lung injury, an effect attributed to reduced bioavailability of angiotensin II. Since angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7), we hypothesized that this effect is alternatively mediated by angiotensin-(1-7) and activation of its receptor(s).


METHODS
To test this hypothesis, we investigated the effects of intravenously infused angiotensin-(1-7) in three experimental models of acute lung injury.


METHODS
Animal research laboratory.


METHODS
Male Sprague-Dawley rats, Balb/c mice, and C57Bl6/J mice.


METHODS
Angiotensin-(1-7) was administered with ventilator- or acid aspiration-induced lung injury in mice or 30 minutes after oleic acid infusion in rats. In vitro, the effect of angiotensin-(1-7) on transendothelial electrical resistance of human pulmonary microvascular endothelial cells was analyzed.


RESULTS
Infusion of angiotensin-(1-7) starting 30 minutes after oleic acid administration protected rats from acute lung injury as evident by reduced lung edema, myeloperoxidase activity, histological lung injury score, and pulmonary vascular resistance while systemic arterial pressure was stabilized. Such effects were largely reproduced by the nonpeptidic angiotensin-(1-7) analog AVE0991. Infusion of angiotensin-(1-7) was equally protective in murine models of ventilator- or acid aspiration-induced lung injury. In the oleic acid model, the two distinct angiotensin-(1-7) receptor blockers A779 and D-Pro-angiotensin-(1-7) reversed the normalizing effects of angiotensin-(1-7) on systemic and pulmonary hemodynamics, but only D-Pro-angiotensin-(1-7) blocked the protection from lung edema and protein leak, whereas A779 restored the infiltration of neutrophils. Rats were also protected from acute lung injury by the AT1 antagonist irbesartan; however, this effect was again blocked by A779 and D-Pro-angiotensin-(1-7). In vitro, angiotensin-(1-7) protected pulmonary microvascular endothelial cells from thrombin-induced barrier failure, yet D-Pro-angiotensin-(1-7) or NO synthase inhibition blocked this effect.


CONCLUSIONS
Angiotensin-(1-7) or its analogs attenuate the key features of acute lung injury and may present a promising therapeutic strategy for the treatment of this disease.
1Department of Physiology, Charité-Universitätsmedizin BerlinBerlin, Germany. 2Department of Cardiac Pathobiology, Excellencecluster Cardio-Pulmonary SystemGießen, Germany. 3Department Nephrology-MK3, University Hospital Dresden, Dresden, Germany. 4The Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Canada. 5Medical Faculty Mannheim, University Heidelberg, Institute of Experimental, Clinical Pharmacology & Toxicology, Mannheim, Germany. 6Centre for Fetal Medicine, Department Pediatric Surgery & Department Obstetrics, Division of Women and Child Health, University Leipzig, Leipzig, Germany. 7Department of Pharmacology and Therapeutics, School of Medicine, University College Cork, Cork, Ireland 8Department of Physiology, University of Toronto, Ontario, Canada. 9Department of Surgery, University of Toronto, Ontario, Canada.
Nadine
N
Klein
Florian
F
Gembardt
Stephanie
S
Supé
Stephanie M
SM
Kaestle
Hannah
H
Nickles
Lasti
L
Erfinanda
Xiaohong
X
Lei
Jun
J
Yin
Liming
L
Wang
Michael
M
Mertens
Katalin
K
Szaszi
Thomas
T
Walther
Wolfgang M
WM
Kuebler
D055371:Acute Lung Injury / Q000503:physiopathology / Q000517:prevention & control*; D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D017097:Electric Impedance; D042783:Endothelial Cells; D006439:Hemodynamics; D007093:Imidazoles / Q000494:pharmacology; D000077405:Irbesartan; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism*; D015656:Respiratory Mechanics; D013777:Tetrazoles / Q000494:pharmacology
C092006:7-Ala-angiotensin (1-7); C469726:AVE 0991; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; C472420:D-Pro7-Ang-(1-7); D007093:Imidazoles; D010446:Peptide Fragments; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7); D000077405:Irbesartan