Angiotensin-(1-7) Protects From Experimental Acute Lung Injury

被引：82

作者：

Klein, Nadine ^{[1
]}

Gembardt, Florian ^{[2
,3
]}

Supe, Stephanie ^{[1
]}

Kaestle, Stephanie M. ^{[1
]}

Nickles, Hannah ^{[1
]}

Erfinanda, Lasti ^{[1
]}

Lei, Xiaohong ^{[1
]}

Yin, Jun ^{[4
]}

Wang, Liming ^{[4
]}

Mertens, Michael ^{[1
]}

Szaszi, Katalin ^{[4
]}

Walther, Thomas ^{[5
,6
,7
,8
]}

Kuebler, Wolfgang M. ^{[1
,4
,9
,10
]}

机构：

[1] Charite, Dept Physiol, D-13353 Berlin, Germany

[2] Excellencecluster Cardiopulm Syst, Dept Cardiac Pathobiol, Giessen, Germany

[3] Univ Hosp Dresden, Dept Nephrol MK3, Dresden, Germany

[4] St Michaels Hosp, Li Ka Shing Knowledge Inst, Keenan Res Ctr, Toronto, ON M5B 1W8, Canada

[5] Heidelberg Univ, Med Fac Mannheim, Inst Expt, Mannheim, Germany

[6] Univ Leipzig, Ctr Fetal Med, D-04109 Leipzig, Germany

[7] Univ Leipzig, Dept Obstet, Div Women & Child Hlth, D-04109 Leipzig, Germany

[8] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland

[9] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A1, Canada

[10] Univ Toronto, Dept Surg, Toronto, ON M5S 1A1, Canada

来源：

CRITICAL CARE MEDICINE | 2013年 / 41卷 / 11期

关键词：

acute lung injury; angiotensin-(1-7); angiotensin-(1-7) receptor blocker; inflammation; permeability; renin-angiotensin system; RESPIRATORY-DISTRESS-SYNDROME; COUPLED-RECEPTOR MAS; CONVERTING-ENZYME; PULMONARY-HYPERTENSION; NITRIC-OXIDE; ENDOTHELIAL FUNCTION; ANTAGONIST; BRAIN; RESENSITIZATION; POLYMORPHISM;

D O I：

10.1097/CCM.0b013e31828a6688

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

Objectives: 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). Design: To test this hypothesis, we investigated the effects of intravenously infused angiotensin-(1-7) in three experimental models of acute lung injury. Setting: Animal research laboratory. Subjects: Male Sprague-Dawley rats, Balb/c mice, and C57Bl6/J mice. Interventions: 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. Measurements and Main 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(7)-angiotensin-(1-7) reversed the normalizing effects of angiotensin-(1-7) on systemic and pulmonary hemodynamics, but only d-Pro(7)-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 AT(1) antagonist irbesartan; however, this effect was again blocked by A779 and d-Pro(7)-angiotensin-(1-7). In vitro, angiotensin-(1-7) protected pulmonary microvascular endothelial cells from thrombin-induced barrier failure, yet d-Pro(7)-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.

引用

页码：E334 / E343

页数：10

共 44 条

[1] ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS [J].