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. 2022 Sep 1;50(9):e696-e706.
doi: 10.1097/CCM.0000000000005495. Epub 2022 Feb 22.

Tidal Volume-Dependent Activation of the Renin-Angiotensin System in Experimental Ventilator-Induced Lung Injury

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
Affiliations

Tidal Volume-Dependent Activation of the Renin-Angiotensin System in Experimental Ventilator-Induced Lung Injury

Xinjun Mao et al. Crit Care Med. .

Abstract

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 (LV T , 6 mL/kg), high tidal volume (HV T , 15 mL/kg), or very high tidal volume (VHV T , 30 mL/kg) for 4 hours, or killed after 3 minutes (sham). Additional VHV T 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 HV T 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 HV T group, whereas classical RAS activation prevailed with VHV T ventilation. Ang 1-7 or captopril protected from VILI primarily by modifying the systemic RAS profile.

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Conflict of interest statement

Dr. Ullrich reports travel expenses and honoraria from Biotest, grants from CCORE, Bayer AG, and Biotest, holds a patent (EP 151897774, minimally invasive liquid lung) and equity in CCORE Technology, a medical device company that develops minimally invasive blood purification devices. Dr. Krenn received funding from Apeptico GmbH and Biotest GmbH. Drs. Poglitsch and Domenig are employed at Attoquant Diagnostics. Dr. Ullrich’s institution received funding from Apeptico, Bayer AG, Philips, and Biotest; he received funding from Biotest, F4 Pharma, and CCORE Technologies. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Comment in

  • The Renin-Angiotensin System in Acute Lung Injury.
    Lawler PR, Derde LPG, McVerry BJ, Russell JA, van de Veerdonk FL. Lawler PR, et al. Crit Care Med. 2022 Sep 1;50(9):1411-1415. doi: 10.1097/CCM.0000000000005567. Epub 2022 Aug 15. Crit Care Med. 2022. PMID: 35984058 No abstract available.

References

    1. Madahar P, Beitler JR: Emerging concepts in ventilation-induced lung injury. F1000Res 2020; 9:F1000 Faculty Rev-222
    1. Baumgardner JE, Markstaller K, Pfeiffer B, et al.: Effects of respiratory rate, plateau pressure, and positive end-expiratory pressure on PaO2 oscillations after saline lavage. Am J Respir Crit Care Med 2002; 166:1556–1562
    1. Lanspa MJ, Peltan ID, Jacobs JR, et al.: Driving pressure is not associated with mortality in mechanically ventilated patients without ARDS. Crit Care 2019; 23:424
    1. Amato MB, Meade MO, Slutsky AS, et al.: Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015; 372:747–755
    1. Aoyama H, Pettenuzzo T, Aoyama K, et al.: Association of driving pressure with mortality among ventilated patients with acute respiratory distress syndrome: A systematic review and meta-analysis. Crit Care Med 2018; 46:300–306

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