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Hyperoxia provokes a time- and dose-dependent inflammatory response in mechanically ventilated mice, irrespective of
Hendrik J F Helmerhorst1,2,3, Laura R A Schouten4,5, Gerry T M Wagenaar6
1Department of Intensive Care Medicine, Leiden University Medical Center, Post Box 9600, 2300 RC, Leiden, The Netherlands. H.J.F.Helmerhorst@lumc.nl.
Background:
Mechanical 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.
Methods:
Healthy 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.
Results:
Mechanical 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.
Conclusions:
We 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.
Insights
Mechanical ventilation and high oxygen levels worsen lung injury in mice. Longer ventilation times and higher oxygen concentrations increase inflammation and immune cell response in the lungs.
Area of Science:
- Pulmonary Medicine
- Critical Care Medicine
- Immunology
Background:
- Mechanical ventilation and hyperoxia can independently cause lung injury and inflammation.
- Understanding the combined effects is crucial for optimizing patient care.
Purpose of the Study:
- To investigate the time- and dose-dependent effects of supplemental oxygen during mechanical ventilation in mice.
- To elucidate the impact of varying fractions of inspired oxygen (FiO2) and ventilation duration on lung injury and inflammation.
Main Methods:
- 100 mice were mechanically ventilated for 8 or 12 hours with varying FiO2 (30%, 50%, 90%) and tidal volumes.
- Arterial blood, bronchoalveolar lavage fluid (BALf), and tissues were collected for analysis.
- Lung injury scores, protein content, cell counts, and cytokine/chemokine levels were assessed.
Main Results:
- Mechanical ventilation significantly increased lung injury scores, protein content, and inflammatory cells (neutrophils) in BALf.
- Prolonged ventilation (12h) with high FiO2 (90%) elevated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-10, MCP-1) and HMGB-1.
- Differences in tidal volume had minimal impact, and effects at 8h ventilation were less pronounced.
Conclusions:
- Severe hyperoxia and prolonged mechanical ventilation exacerbate vascular leakage and pro-inflammatory responses in the lungs.
- High oxygen concentrations and extended ventilation duration induce a time-dependent immune response, increasing neutrophils, cytokines, and chemokines.
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