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Tidal Volume–Dependent Activation of the Renin-Angiotensin System in Experimental Ventilator-Induced Lung Injury*
Critical Care Medicine ( IF 7.7 ) Pub Date : 2022-09-01 , DOI: 10.1097/ccm.0000000000005495
Xinjun Mao 1 , Katharina Krenn 1 , Thomas Tripp 1 , Verena Tretter 1 , Roman Reindl-Schwaighofer 2 , Felix Kraft 1 , Bruno K Podesser 3 , Yi Zhu 1, 4 , Marko Poglitsch 5 , Oliver Domenig 5 , Dietmar Abraham 6 , Roman Ullrich 1
Affiliation  

OBJECTIVES: 

Ventilator-induced lung injury (VILI) is a major contributor to morbidity and mortality in critically ill patients. Mechanical damage to the lungs is potentially aggravated by the activation of the renin-angiotensin system (RAS). This article describes RAS activation profiles in VILI and discusses the effects of angiotensin (Ang) 1–7 supplementation or angiotensin-converting enzyme (ACE) inhibition with captopril as protective strategies.

DESIGN: 

Animal study.

SETTING: 

University research laboratory.

SUBJECTS: 

C57BL/6 mice.

INTERVENTIONS: 

Anesthetized mice (n = 12–18 per group) were mechanically ventilated with low tidal volume (LVT, 6 mL/kg), high tidal volume (HVT, 15 mL/kg), or very high tidal volume (VHVT, 30 mL/kg) for 4 hours, or killed after 3 minutes (sham). Additional VHVT groups received infusions of 60 μg/kg/hr Ang 1–7 or a single dose of 100 mg/kg captopril.

MEASUREMENTS AND MAIN RESULTS: 

VILI was characterized by increased bronchoalveolar lavage fluid levels of interleukin (IL)-6, keratinocyte-derived cytokine, and macrophage inflammatory protein-2 (MIP2). The Ang metabolites in plasma measured with liquid chromatography tandem mass spectrometry showed a strong activation of the classical (Ang I, Ang II) and alternative RAS (Ang 1–7, Ang 1–5), with highest concentrations found in the HVT group. Although the lung-tissue ACE messenger RNA expression was unchanged, its protein expression showed a dose-dependent increase under mechanical ventilation. The ACE2 messenger RNA expression decreased in all ventilated groups, whereas ACE2 protein levels remained unchanged. Both captopril and Ang 1–7 led to markedly increased Ang 1–7 plasma levels, decreased Ang II levels, and ACE activity (Ang II/Ang I ratio), and effectively prevented VILI.

CONCLUSIONS: 

VILI is accompanied by a strong activation of the RAS. Based on circulating Ang metabolite levels and tissue expression of RAS enzymes, classical ACE-dependent and alternative RAS cascades were activated in the HVT group, whereas classical RAS activation prevailed with VHVT ventilation. Ang 1–7 or captopril protected from VILI primarily by modifying the systemic RAS profile.



中文翻译:

实验性呼吸机引起的肺损伤中肾素-血管紧张素系统的潮气量依赖性激活*

目标: 

呼吸机引起的肺损伤(VILI)是危重患者发病率和死亡率的主要因素。肾素-血管紧张素系统 (RAS) 的激活可能会加重肺部的机械损伤。本文描述了 VILI 中的 RAS 激活谱,并讨论了血管紧张素 (Ang) 1-7 补充剂或使用卡托普利抑制血管紧张素转换酶 (ACE) 作为保护策略的效果。

设计: 

动物研究。

环境: 

大学研究实验室。

主题: 

C57BL/6 小鼠。

干预: 

麻醉小鼠(每组n = 12-18)用低潮气量(LV T,6 mL/kg)、高潮气量(HV T,15 mL/kg)或非常高潮气量(VHV T, 30 mL/kg) 4 小时,或 3 分钟后杀死(假)。其他 VHV T组接受 60 μg/kg/hr Ang 1-7 或单剂量 100 mg/kg 卡托普利的输注。

测量和主要结果: 

VILI 的特点是支气管肺泡灌洗液中白细胞介素 (IL)-6、角质形成细胞衍生的细胞因子和巨噬细胞炎症蛋白-2 (MIP2) 水平升高。用液相色谱串联质谱法测量的血浆中的 Ang 代谢物显示经典(Ang I、Ang II)和替代 RAS(Ang 1-7、Ang 1-5)的强烈激活,在 HV T中发现浓度最高团体。尽管肺组织 ACE 信使 RNA 表达没有变化,但其蛋白质表达在机械通气下呈剂量依赖性增加。所有通气组的 ACE2 信使 RNA 表达均下降,而 ACE2 蛋白水平保持不变。卡托普利和 Ang 1-7 均导致 Ang 1-7 血浆水平显着升高,Ang II 水平和 ACE 活性(Ang II/Ang I 比值)降低,并有效预防 VILI。

结论: 

VILI 伴随着 RAS 的强烈激活。根据循环 Ang 代谢物水平和 RAS 酶的组织表达,在 HV T组中激活了经典的 ACE 依赖性和替代 RAS 级联反应,而经典的 RAS 激活在 VHV T通气中占优势。Ang 1-7 或卡托普利主要通过修改全身 RAS 配置文件来保护免受 VILI。

更新日期:2022-08-18
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