The circadian rhythm regulates the severity of ventilator-induced lung injury

Abstract

Background: Recent studies have provided evidence that the circadian rhythm (CR) is an important regulator of the innate immune response in the lung. As most patients in acute repiratory failure undergo continuous therapeutic/nursing interventions in the intensive care unit (ICU), the disturbance of their CR might be a critical factor for their outcome. Whether the CR regulates the pathophysiology of ventilator-induced lung injury (VILI) is currently unknown. Methods: In this study, we explored the influence of CR in the development of murine VILI. VILI was induced by high tidal volume ventilation (HVt:34ml/kg, Inspiration:Expiration(I:E)-Ratio 1:2, 4h). For survival studies, high strain HVt ventilation (HVt:34ml/kg, I:E-Ratio 1:1) was used. mechanical ventilation (MV) was initiated at dawn (Zeitgeber time (ZT) 0) or at dusk (ZT12). To quantify VILI, lung compliance, pulmonary permeability, neutrophil recruitment, and markers of pulmonary inflammation were measured. Results: Animals ventilated with HVt (I:E 1:2) at ZT0 showed higher inflammatory cytokine levels, slightly decreased lung compliance and increased number of neutrophils compared with the ZT12 group. Escalating the ventilation strategy (HVt 1:1) at ZT0 led to a significant worsening of oxygenation, decrease of pulmonary compliance and increase in the levels of pro-inflammatory cytokines compared to ZT12. Survival in the ZT0 group was significantly reduced. Conclusion: Our results suggest that the time-of-day when mice undergo MV is a critical factor for the pulmonary immune response and determines the severity of VILI. Future studies may address whether prolonged day-time, frequently observed in ICUs, influences VILI.