title: Effects of nebulized diethylenetetraamine-NONOate in a mouse model of acute Pseudomonas aeruginosa pneumonia.
abstract: 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.
authors.affiliation: 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.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Dukelow
authors.forename: Sean
authors.initials: S
authors.lastname: Weicker
authors.forename: Tim A
authors.initials: TA
authors.lastname: Karachi
authors.forename: Habib M
authors.initials: HM
authors.lastname: Razavi
authors.forename: David G
authors.initials: DG
authors.lastname: McCormack
authors.forename: Mariamma G
authors.initials: MG
authors.lastname: Joseph
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mehta
mesh_terms: 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
chemical_list: D000336:Aerosols; D006834:Hydrazines; D009566:Nitrates; D009573:Nitrites; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide