Nitric Oxide Enhances Bacterial Clearance in Hyperoxia
Lin Mantell, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences
Abstract: A significant number of patients on ventilator develop ventilator-associated pneumonia (VAP) and inflammatory lung injury. Despite the advancement of antimicrobial therapy, VAP results in significant morbidity and mortality in these patients. Previously, studies including ours have demonstrated exposure to prolonged hyperoxia results in macrophage dysfunction. In this study, we observed that prolonged hyperoxia suppressed levels of airway NO. We tested whether administration of exogenous NO enhances the host’s ability to clear the bacteria. C57BL/6 mice were randomized to receive either intranasal DETA-NONOate (D-NO), a NO donor, or control solution, exposed to ≥99.0% O2, and then inoculated with intranasal instillation of PA. Treatment with D-NO improved the survival, decreased bacterial load in the lung and mitigated hyperoxia/PA-induced lung injury in a dose-dependent manner. Moderate concentrations of D-NO significantly rescued hyperoxia-suppressed macrophage functions in RAW 264.7 cells exposed to 95% O2. However, macrophages exposed to D-NO at concentrations of 150 μM or higher underwent cell death. These results indicate that exogenous NO might provide a novel therapeutic approach in preventing patients on ventilator from developing VAP.