Effects of nebulized diethylenetetraamine-NONOate in a mouse model of acute Pseudomonas aeruginosa pneumonia.
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.


METHODS
Randomized, controlled study.


METHODS
Male C57Bl/6 mice.


METHODS
Pneumonia was induced by intratracheal instillation of P aeruginosa (3 x 10(7) CFU in 50 microL). Pneumonia and sham mice were randomized to receive no treatment, nebulized DETA-NO (12.5 or 125 micromol) at 4 h and 12 h, or continuous iNO for 24 h (10 or 40 ppm) until they were killed at 24 h.


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 microM; at baseline, 14 +/- 3 microM; 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.
Dukelow
Adam M
AM
A.C. Burton Vascular Biology Group, Lawson Health Research Institute, Respirology Division, London Health Sciences Center-Victoria South Street Campus, 375 South Street, London, Ontario, Canada N6A 4G5.
Weicker
Sean
S
Karachi
Tim A
TA
Razavi
Habib M
HM
McCormack
David G
DG
Joseph
Mariamma G
MG
Mehta
Sanjay
S
D000208:Acute Disease; D000336:Aerosols; D000818:Animals; D004195:Disease Models, Animal; D006834:Hydrazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000008:administration & dosage / Q000032:analysis; D009573:Nitrites / Q000097:blood; D009603:Nitroso Compounds; D018410:Pneumonia, Bacterial / Q000188:drug therapy*; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D011897:Random Allocation
D000336:Aerosols; D006834:Hydrazines; D009566:Nitrates; D009573:Nitrites; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide