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.
Crit Care Med. 2013 Nov;41(11):e334-43. doi: 10.1097/CCM.0b013e31828a6688.
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).
To test this hypothesis, we investigated the effects of intravenously infused angiotensin-(1-7) in three experimental models of acute lung injury.
Animal research laboratory.
Male Sprague-Dawley rats, Balb/c mice, and C57Bl6/J mice.
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.
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.
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.
最近的研究表明，重组血管紧张素转换酶 2 可保护小鼠免受急性肺损伤，其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)，我们假设这种作用可通过血管紧张素-(1-7)替代介导，并激活其受体。
为了验证这一假设，我们在三种急性肺损伤的实验模型中研究了静脉内输注血管紧张素-(1-7)的作用。
动物研究实验室。
雄性 Sprague-Dawley 大鼠、Balb/c 小鼠和 C57Bl6/J 小鼠。
在小鼠中，给予血管紧张素-(1-7)输注，同时给予呼吸机或酸吸入诱导肺损伤，或在大鼠中给予油酸后 30 分钟给予血管紧张素-(1-7)。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。
油酸给药后 30 分钟开始输注血管紧张素-(1-7)可保护大鼠免受急性肺损伤，表现为肺水肿、髓过氧化物酶活性、组织学肺损伤评分和肺血管阻力降低，同时稳定全身动脉压。非肽类血管紧张素-(1-7)类似物 AVE0991 也可重现这种作用。血管紧张素-(1-7)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)受体阻滞剂 A779 和 D-Pro-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-血管紧张素-(1-7)阻断了肺水肿和蛋白渗漏的保护作用，而 A779 则恢复了中性粒细胞的浸润。AT1 拮抗剂厄贝沙坦也可保护大鼠免受急性肺损伤；然而，这种作用再次被 A779 和 D-Pro-血管紧张素-(1-7)阻断。体外，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破坏，然而 D-Pro-血管紧张素-(1-7)或一氧化氮合酶抑制阻断了这种作用。
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，可能为治疗这种疾病提供一种有前途的治疗策略。
