Therapeutic time window for angiotensin-(1-7) in acute lung injury
Therapeutic time window for angiotensin-(1-7) in acute lung injury
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DOI：
10.1111/bph.13462
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发表时间：
2016-05-01
影响因子：
7.3
通讯作者：
Walther, Thomas
中科院分区：
文献类型：
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作者：
Supe, Stefanie;Kohse, Franziska;Walther, Thomas
背景和结论目前对急性呼吸窘迫综合征尚无经证实的药物治疗。最近，我们和其他人发现七肽血管紧张素-（1-7）[Ang-（1-7）]在急性肺损伤（ALI）的临床前模型中显示出显著的有益作用。实验方法在雄性Sprague-Dawley大鼠中，在诱导ALI之前或之后的四个不同的时间窗内检查静脉输注Ang-（1-7）的作用。连续监测血液动力学效应，并测量屏障功能丧失、炎症和肺肽酶活性作为实验终点。KEY TSANG-（1-7）输注在OA输注30分钟后立即开始持续输注直至实验结束（30-240分钟）时提供了对实验性ALI的最佳保护。预处理（OA前-60至0分钟）和短期治疗（30-90分钟）也具有有益效果，尽管不如最佳治疗窗所达到的效果明显。OA治疗结束后60 min开始输注Ang-（1-7）（90-240 min）并不保护屏障功能或血流动力学，但仍然降低髓过氧化物酶活性和增加ACE 2/ACE活性比值分别.CONCLUSIONS AND IMPLITIONSOUR的研究结果表明，ALI后早期开始治疗和持续给药对Ang-（1-7）的最佳治疗效果最有利。治疗实验性ALI，并据此推测，在临床急性呼吸窘迫综合征。
BACKGROUND AND PURPOSEThere is presently no proven pharmacological therapy for the acute respiratory distress syndrome. Recently, we and others discovered that the heptapeptide angiotensin-(1-7) [Ang-(1-7)] shows significant beneficial effects in preclinical models of acute lung injury (ALI). Here, we aimed to identify the best time window for Ang-(1-7) administration to protect rats from oleic acid (OA) induced ALI.EXPERIMENTAL APPROACHThe effects of i.v. infused Ang-(1-7) were examined over four different time windows before or after induction of ALI in male Sprague-Dawley rats. Haemodynamic effects were continuously monitored, and loss of barrier function, inflammation and lung peptidase activities were measured as experimental endpoints.KEY RESULTSAng-(1-7) infusion provided the best protection against experimental ALI when administered by continuous infusion starting immediately after 30 min OA infusion till the end of the experiment (30-240 min). Both pretreatment (-60 to 0 min before OA) and short-term therapy (30-90 min) also had beneficial effects although less pronounced than the effects achieved with the optimal therapy window. Starting infusion of Ang-(1-7) 60 min after the end of OA treatment (90-240 min) did not protect barrier function or haemodynamics but still reduced myeloperoxidase activity and increased ACE2/ACE activity ratio respectively.CONCLUSIONS AND IMPLICATIONSOur findings indicate that early initiation of therapy after ALI and continuous drug delivery are most beneficial for optimal therapeutic efficiency of Ang-(1-7) treatment in experimental ALI and, presumably accordingly, in clinical acute respiratory distress syndrome.