Angiotensin-(1-7) Protects From Experimental Acute Lung Injury
Angiotensin-(1-7) Protects From Experimental Acute Lung Injury
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DOI：
10.1097/ccm.0b013e31828a6688
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发表时间：
2013-11-01
影响因子：
8.8
通讯作者：
Kuebler, Wolfgang M.
中科院分区：
文献类型：
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作者：
Klein, Nadine;Gembardt, Florian;Kuebler, Wolfgang M.
目的：最近，重组血管紧张素转换酶2被证明可以保护小鼠免受急性肺损伤，这种作用归因于血管紧张素II的生物利用度降低。由于血管紧张素转换酶2将血管紧张素II代谢为血管紧张素-（1-7），我们假设这种作用是由血管紧张素-（1-7）及其受体的激活交替介导的。设计：为了验证这一假设，我们研究了静脉输注血管紧张素-（1-7）在三种急性肺损伤实验模型中的作用。干预措施：在小鼠中给予血管紧张素-（1-7）与呼吸机或酸吸入诱导的肺损伤，或在大鼠中给予油酸后30分钟。在体外，分析血管紧张素-（1-7）对人肺微血管内皮细胞跨内皮电阻的影响。测量和主要结果：在给予油酸后30分钟开始输注血管紧张素-（1-7）保护大鼠免受急性肺损伤，这通过减少肺水肿、髓过氧化物酶活性、组织学肺损伤评分、和肺血管阻力，同时稳定体循环动脉压。这种效应在很大程度上由非肽类血管紧张素-（1-7）类似物AVE 0991重现。血管紧张素-（1-7）的输注在呼吸机或酸吸入诱导的肺损伤的小鼠模型中同样具有保护作用。在油酸模型中，两种不同的血管紧张素-（1-7）受体阻断剂A779和d-Pro（7）-血管紧张素-（1 -7）逆转了血管紧张素-（1-7）对全身和肺血流动力学的正常化作用，但只有d-Pro（7）-血管紧张素-（1-7）阻断了对肺水肿和蛋白渗漏的保护，而A779恢复了中性粒细胞的浸润。AT（1）拮抗剂厄贝沙坦也能保护大鼠免受急性肺损伤;然而，这种作用再次被A779和d-Pro（7）-血管紧张素-（1-7）阻断。在体外实验中，血管紧张素-（1-7）可保护肺微血管内皮细胞免受凝血酶诱导的屏障功能障碍，但d-Pro（7）-血管紧张素-（1-7）或NO合酶抑制剂可阻断这种作用。结论：血管紧张素-（1-7）或其类似物可减轻急性肺损伤的关键特征，并可能为治疗这种疾病提供一种有前途的治疗策略。
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.