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(Chest. 2002;122:2127-2136.)
© 2002 American College of Chest Physicians

Effects of Nebulized Diethylenetetraamine-NONOate in a Mouse Model of Acute Pseudomonas aeruginosa Pneumonia*

Adam M. Dukelow, BSc; Sean Weicker, MSc; Tim A. Karachi, MD; Habib M. Razavi, MSc; David G. McCormack, MD; Mariamma G. Joseph, MD and Sanjay Mehta, MD

* From the A.C. Burton Vascular Biology Group (Mr. Dukelow), Lawson Health Research Institute, Respirology Division, London Health Sciences Center, London, ON, Canada; and the Departments of Medicine (Drs. Karachi, McCormack, and Mehta), Pathology (Dr. Joseph), and Pharmacology/Toxicology (Mr. Weicker and Mr. Razavi), University of Western Ontario, London, ON, Canada.

Correspondence to: Sanjay Mehta, MD, Respirology Division, London Health Sciences Center-Victoria South Street Campus, 375 South St, London, ON, Canada N6A 4G5; e-mail: sanjay.mehta{at}lhsc.on.ca

Objective: Endogenous and exogenous nitric oxide (NO) may have important antibacterial effects in patients with pneumonia. NO administration has been limited to the continuous inhalation of gas-phase NO (ie, inhaled NO [iNO]). Intermittent nebulization of NONOates, novel NO donors, may permit the continuous intrapulmonary delivery of NO. Thus, we assessed the effects of nebulized diethylenetetraamine-NONOate (DETA-NO) in a model of acute Pseudomonas aeruginosa pneumonia.

Design: Randomized, controlled study.

Subjects: Male C57Bl/6 mice.

Interventions: Pneumonia was induced by intratracheal instillation of P aeruginosa (3 x 107 CFU in 50 µL). Pneumonia and sham mice were randomized to receive no treatment, nebulized DETA-NO (12.5 or 125 µmol) at 4 h and 12 h, or continuous iNO for 24 h (10 or 40 ppm) until they were killed at 24 h.

Main results: The nebulization of DETA-NO was associated with a marked increase in mean (± SEM) exhaled NO levels (after nebulization, 484 ± 34 parts per billion [ppb]; baseline, 13.4 ± 0.4 ppb; p < 0.01) and plasma levels of nitrites/nitrates (after nebulization, 73 ± 28 µM; at baseline, 14 ± 3 µM; p < 0.05). Nebulized DETA-NO decreased the pulmonary bacterial load in mice with pneumonia by 65 ± 19% (p < 0.05 vs untreated mice) but had no effect on pulmonary leukocyte infiltration. Although the growth of P aeruginosa colonies in vitro was impaired on exposure to DETA-NO, growth was similarly impaired by exposure to DETA nucleophile/backbone alone.

Conclusions: The nebulization of DETA-NO provides a method for the prolonged intrapulmonary delivery of NO. The antibacterial effect of DETA-NO in vivo and in vitro is due, in large part, to the DETA nucleophile moiety and is independent of NO, suggesting a limited therapeutic role for exogenous NO in pneumonia.

Key Words: exhaled nitric oxide • inhaled nitric oxide • lung inflammation • nitric oxide • nitric oxide donors • nitrites/nitrates






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