Abstract
IntroductionPositive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human IL-8, and neutrophil infiltration. Hyperoxia has been shown to increase ventilator-induced lung injury, but the mechanisms regulating interaction between a large tidal volume and hyperoxia are unclear. We hypothesized that large tidal volume ventilation using hyperoxia would increase MIP-2 production and neutrophil infiltration via the serine/threonine kinase/protein kinase B (Akt) pathway and the endothelial nitric oxide synthase (eNOS) pathway.MethodsC57BL/6 mice were exposed to large tidal volume (30 ml/kg) mechanical ventilation with room air or hyperoxia for 1–5 hours.ResultsLarge tidal volume ventilation using hyperoxia induced neutrophil migration into the lung, MIP-2 production, and Akt and eNOS activation in a time-dependent manner. Both the large tidal volume ventilation of Akt mutant mice and the pharmacological inhibition of Akt with LY294002 attenuated neutrophil sequestration, MIP-2 protein production, and Akt and eNOS activation.ConclusionWe conclude that hyperoxia increased large tidal volume-induced MIP-2 production and neutrophil influx through activation of the Akt and eNOS pathways.
Highlights
Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human IL-8, and neutrophil infiltration
We conclude that hyperoxia increased large tidal volume-induced MIP-2 production and neutrophil influx through activation of the Akt and endothelial nitric oxide synthase (eNOS) pathways
Physiologic data As we have shown previously [12], in the group of animals used for these experiments there was no statistical difference in pH, PaO2, PaCO2, mean arterial pressure, and peak inspiratory pressure found at the beginning versus at the end of 5 hours mechanical ventilation (Table 1)
Summary
Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human IL-8, and neutrophil infiltration. Mechanical ventilation with large tidal volume (VT) causes acute lung injury (ventilator-induced lung injury (VILI)) characterized by an inflammatory response morphologically and histologically indistinguishable from that caused by bacterial lipopolysaccharide [7,8]. Both large VT ventilation and hyperoxia alone can lead to the production of inflammatory cytokines including TNFα, IL-1β, and murine macrophage inflammatory protein-2 (MIP-2) [9,10,11], to airway apoptosis [12], to lung neutrophil influx [12], and to capillary leak [12].
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