• HelmerhorstHendrik J FHJFDepartment of Intensive Care Medicine, Leiden University Medical Center, Post Box 9600, 2300 RC, Leiden, The Netherlands. H.J.F.Helmerhorst@lumc.nl.Department of Anesthesiology, Leiden University Medical Center, Leiden, The Nether, SchoutenLaura R ALRALaboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, Amsterdam, The Netherlands.Department of Intensive Care Medicine, Academic Medical Center, Amsterdam, The Netherlands., WagenaarGerry T MGTMDepartment of Pediatrics, Laboratory of Neonatology, University Medical Center Leiden, Leiden, The Netherlands., Nicole P Juffermans, RoelofsJoris J T HJJTHDepartment of Pathology, Academic Medical Center, Amsterdam, The Netherlands., Marcus J Schultz, Evert de Jonge, and David J van Westerloo.
• Department of Intensive Care Medicine, Leiden University Medical Center, Post Box 9600, 2300 RC, Leiden, The Netherlands. H.J.F.Helmerhorst@lumc.nl.
• Intensive Care Med Exp. 2017 Dec 1; 5 (1): 27.

BackgroundMechanical ventilation and hyperoxia have the potential to independently promote lung injury and inflammation. Our purpose was to study both time- and dose-dependent effects of supplemental oxygen in an experimental model of mechanically ventilated mice.MethodsHealthy male C57Bl/6J mice, aged 9-10 weeks, were intraperitoneally anesthetized and randomly assigned to the mechanically ventilated group or the control group. In total, 100 mice were tracheotomized and mechanically ventilated for either 8 or 12 h after allocation to different settings for the applied fractions of inspired oxygen (FiO2, 30, 50, or 90%) and tidal volumes (7.5 or 15 ml/kg). After euthanisation arterial blood, bronchoalveolar lavage fluid (BALf) and tissues were collected for analyses.ResultsMechanical ventilation significantly increased the lung injury score (P < 0.05), mean protein content (P < 0.001), and the mean number of cells (P < 0.01), including neutrophils in BALf (P < 0.001). In mice ventilated for 12 h, a significant increase in TNF-α, IFN-γ, IL-1β, IL-10, and MCP-1 (P < 0.01) was observed with 90% FiO2, whereas IL-6 showed a decreasing trend (P for trend = 0.03) across FiO2 groups. KC, MIP-2, and sRAGE were similar between FiO2 groups. HMGB-1 was significantly higher in BALf of mechanically ventilated mice compared to controls and showed a gradual increase in expression with increasing FiO2. Cytokine and chemokine levels in BALf did not markedly differ between FiO2 groups after 8 h of ventilation. Differences between the tidal volume groups were small and did not appear to significantly interact with the oxygen levels.ConclusionsWe demonstrated a severe vascular leakage and a pro-inflammatory pulmonary response in mechanically ventilated mice, which was enhanced by severe hyperoxia and longer duration of mechanical ventilation. Prolonged ventilation with high oxygen concentrations induced a time-dependent immune response characterized by elevated levels of neutrophils, cytokines, and chemokines in the pulmonary compartment.

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