Sex- and age-related differences in LPS-induced lung injury: establishing a mouse intensive care unit.

Background

Mouse models are widely used to establish new therapy concepts for acute lung injury, but the transfer of therapeutic approaches into the intensive care unit often failed. To establish a mouse intensive care unit to adequately reflect the patient's situation and to investigate sex- and age-related differences in response to lipopolysaccharide.

Methods

For the establishment of a mouse intensive care unit, young (2-3 months) and old (15-18 months) mice of both sexes received continuous respiratory and cardiovascular monitoring for 6 h. Mimicking an acute lung injury by intratracheal lipopolysaccharide stimulation for 6 or 24 h, the impact of sex and age on survival and physiological parameters was evaluated.

Results

The establishment revealed sex- and age-related differences in physiological responses during mechanical ventilation, with old males requiring more noradrenaline to maintain stable hemodynamics. While young mice, irrespective of sex, developed acute lung injury 24 h after lipopolysaccharide administration, old mice exhibited a rapid systemic response, showing signs of lactic acidosis and endotoxemia. Among these, old females had the highest mortality risk, whereas in old males, mechanical ventilation provided effective support, contributing to improved survival outcomes.

Conclusions

We successfully established a mouse intensive care unit that integrated all critical aspects of a human intensive care unit simultaneously. By highlighting sex- and age-related differences following lipopolysaccharide stimulation and mechanical ventilation, our study underscored the need for diversity in preclinical models to improve translation of findings on critical illnesses like acute lung injury into clinical settings.

COI Statement

Declarations. Ethics approval and consent to participate: All animal experiments were conducted in accordance with the guidelines of the National Institute of Health Guide for Care and Use of Laboratory Animals. The study was approved by the local Animal Care and Use Committee (FK/2012, FK/2039) and followed the ARRIVE guidelines 2.0 [16]. Consent for publication: All authors approved the manuscript for submission. Competing interests: The Department of Anesthesiology, Intensive Care Medicine & Pain Therapy of the University Hospital Frankfurt, Goethe University received support from B. Braun Melsungen, CSL Behring, Fresenius Kabi, and Vifor Pharma for the implementation of Frankfurt’s Patient Blood Management program. KZ has received honoraria for participation in advisory board meetings for Haemonetics and Vifor and received speaker fees from CSL Behring, Masimo, Pharmacosmos, Boston Scientific, Salus, iSEP, Edwards and GE Healthcare. He is the Principal Investigator of the EU-Horizon 2020 project ENVISION (Intelligent plug-and-play digital tool for real-time surveillance of COVID-19 patients and smart decision-making in Intensive Care Units) and Horizon Europe 2021 project COVend (Biomarker and AI-supported FX06 therapy to prevent progression from mild and moderate to severe stages of COVID-19). KZ: KZ leads as CEO the Christoph Lohfert Foundation as well as the Health, Patient Safety & PBM Foundation. PR declares that financial support was received for the research, authorship, and/or publication of this article by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG): projects 251293561 (Collaborative Research Center, CRC 1149), 465409392 (Research Unit, FOR 5417), and 278012962 (Ulm University Research Training Group PULMOSENS, GRK 2203). The remaining authors declare no potential competing interests.

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