Combined angiotensin-converting enzyme and aminopeptidase inhibition for treatment of experimental ventilator-induced lung injury in mice

Xinjun Mao; Verena Tretter; Yi Zhu; Felix Kraft; Benjamin Vigl; Marko Poglitsch; Roman Ullrich; Dietmar Abraham; Katharina Krenn

doi:10.3389/fphys.2023.1109452

Combined angiotensin-converting enzyme and aminopeptidase inhibition for treatment of experimental ventilator-induced lung injury in mice

Front Physiol. 2023 Mar 30:14:1109452. doi: 10.3389/fphys.2023.1109452. eCollection 2023.

Authors

Xinjun Mao^{1

2}, Verena Tretter¹, Yi Zhu^{1

3}, Felix Kraft¹, Benjamin Vigl⁴, Marko Poglitsch⁵, Roman Ullrich^{1

6}, Dietmar Abraham⁷, Katharina Krenn¹

Affiliations

¹ Department of Anesthesia, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria.
² Department of Anesthesiology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
³ Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Alterras Therapeutics GmbH, Vienna, Austria.
⁵ Attoquant Diagnostics GmbH, Vienna, Austria.
⁶ Department of Anesthesiology and Intensive Care Medicine, AUVA Trauma Center Vienna, Vienna, Austria.
⁷ Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.

Abstract

Introduction: Ventilator-induced lung injury (VILI) may aggravate critical illness. Although angiotensin-converting enzyme (ACE) inhibition has beneficial effects in ventilator-induced lung injury, its clinical application is impeded by concomitant hypotension. We hypothesized that the aminopeptidase inhibitor ALT-00 may oppose the hypotension induced by an angiotensin-converting enzyme inhibitor, and that this combination would activate the alternative renin-angiotensin system (RAS) axis to counteract ventilator-induced lung injury. Methods: In separate experiments, C57BL/6 mice were mechanically ventilated with low (LVT, 6 mL/kg) and high tidal volumes (HVT, 30 mL/kg) for 4 h or remained unventilated (sham). High tidal volume-ventilated mice were treated with lisinopril (0.15 μg/kg/min) ± ALT-00 at 2.7, 10 or 100 μg/kg/min. Blood pressure was recorded at baseline and after 4 h. Lung histology was evaluated for ventilator-induced lung injury and the angiotensin (Ang) metabolite profile in plasma (equilibrium levels of Ang I, Ang II, Ang III, Ang IV, Ang 1-7, and Ang 1-5) was measured with liquid chromatography tandem mass spectrometry at the end of the experiment. Angiotensin concentration-based markers for renin, angiotensin-converting enzyme and alternative renin-angiotensin system activities were calculated. Results: High tidal volume-ventilated mice treated with lisinopril showed a significant drop in the mean arterial pressure at 4 h compared to baseline, which was prevented by adding ALT-00 at 10 and 100 μg/kg/min. Ang I, Ang II and Ang 1-7 plasma equilibrium levels were elevated in the high tidal volumes group versus the sham group. Lisinopril reduced Ang II and slightly increased Ang I and Ang 1-7 levels versus the untreated high tidal volumes group. Adding ALT-00 at 10 and 100 μg/kg/min increased Ang I and Ang 1-7 levels versus the high tidal volume group, and partly prevented the downregulation of Ang II levels caused by lisinopril. The histological lung injury score was higher in the high tidal volume group versus the sham and low tidal volume groups, and was attenuated by lisinopril ± ALT-00 at all dose levels. Conclusion: Combined angiotensin-converting enzyme plus aminopeptidase inhibition prevented systemic hypotension and maintained the protective effect of lisinopril. In this study, a combination of lisinopril and ALT-00 at 10 μg/kg/min appeared to be the optimal approach, which may represent a promising strategy to counteract ventilator-induced lung injury that merits further exploration.

Keywords: aminopeptidase; angiotensin-converting enzyme inhibitor; hypotension; renin-angiotensin system; ventilator-induced lung injury.

Grants and funding

The study was funded by the Dept. of Anesthesia and General Intensive Care and grants of Apeptico GmbH and Biotest GmbH to KK as well as grant no. 879941 from the Austrian Research Promotion Agency (FFG) to BV and Alterras Therapeutics GmbH. Alterras Therapeutics GmbH provided the study drugs lisinopril and ALT-00. BV as a shareholder and employee of Alterras Therapeutics GmbH participated in study conceptualization and reviewed and edited the manuscript. BV and Alterras Therapeutics GmbH were not involved in collection and analysis of in vivo data. The funders Apeptico GmbH and Biotest GmbH were not involved in the study design, collection, analysis, and interpretation of data, the writing of this article or the decision to submit it for publication.