Effects of inhaled nitric oxide in a rat model of Pseudomonas aeruginosa pneumonia
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OBJECTIVE: Antimicrobial effects of nitric oxide (NO) have been demonstrated in vitro against a variety of infectious pathogens, yet in vivo evidence of a potential therapeutic role for exogenous NO as an antimicrobial agent is limited. Thus, we assessed the effects of inhaled NO on pulmonary infection, leukocyte infiltration, and NO synthase (NOS) activity in a rat model of Pseudomonas aeruginosa pneumonia. DESIGN: Controlled animal study. SETTING: Research laboratory of an academic institution. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: After intratracheal instillation of either P. aeruginosa or saline (sham), rats were randomly exposed to either 40 ppm of inhaled NO or room air (RA) for 24 hrs before they were killed. MEASUREMENTS AND MAIN RESULTS: Inhaled NO in pneumonia rats markedly reduced pulmonary bacterial load (0.02+/-0.01% vs. 0.99+/-0.59% of bacterial input in pneumonia with room air, p < .05) and pulmonary myeloperoxidase activity, a marker of leukocyte infiltration (21.7+/-3.8 vs. 55.0+/-8.1 units in pneumonia with room air, p < .05), but had no effect on systemic hemodynamics or gas exchange. Pneumonia was associated with enhanced pulmonary NOS activity (8.8+/-2.4 vs. 0.2+/-0.1 pmol citrulline/min/mg protein in sham, p < .01) and increased plasma levels of nitrites/nitrates (NOx-; 45+/-7 vs. 16+/-3 micromol/L in sham, p < .01). Inhaled NO therapy attenuated the pneumonia-induced increase in pulmonary calcium-independent NOS activity (p < .05) and markedly increased plasma NOx- levels. Exposure of P. aeruginosa in culture to 40 ppm of ambient NO confirmed a delayed antibacterial effect of NO in vitro. CONCLUSIONS: Inhaled NO has an important antibacterial effect both in vitro and in vivo against P. aeruginosa and is associated with reduced pulmonary leukocyte infiltration in vivo. These results in a rat model of P. aeruginosa pneumonia suggest that future studies should address the possible clinical effects of inhaled NO therapy in pneumonia.
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