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

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.