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

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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.

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