title: Effects of inhaled nitric oxide in a mouse model of sepsis-induced acute lung injury.
abstract: OBJECTIVE
  Although inhaled nitric oxide transiently improves oxygenation in patients with acute lung injury, it has not affected clinical outcomes. As well, the effects of inhaled nitric oxide on the pathophysiologic features of acute lung injury have not been well defined. Therefore, we assessed the effects of inhaled nitric oxide on the degree of pulmonary inflammation and injury in a mouse model of sepsis-induced acute lung injury.
  
  
  METHODS
  Randomized, controlled animal study.
  
  
  METHODS
  Research laboratory of an academic institution.
  
  
  METHODS
  Male C57Bl/6 mice.
  
  
  METHODS
  Sepsis was induced by cecal ligation and perforation. At the time of surgery, septic and naïve mice were randomized to exposure to either 40 ppm inhaled nitric oxide or room air for 24 hrs before they were killed.
  
  
  RESULTS
  Sepsis-induced acute lung injury was characterized by increased pulmonary myeloperoxidase (68 +/- 13 vs. 13 +/- 3 mU/mg protein in naïve mice, p <.01), pulmonary 8-isoprostane content (627 +/- 51 vs. 88 +/- 20 pg/mg protein in naïve mice, p <.01), and protein in bronchoalveolar lavage fluid (p <.05). Inhaled nitric oxide exposure in septic mice completely abrogated the septic increases in myeloperoxidase activity (p <.05) and pulmonary 8-isoprostane content (p <.05) but had no effect on bronchoalveolar lavage protein. The induction of sepsis also was associated with an increase in pulmonary inducible NO synthase activity (2.8 +/- 0.5 vs. 0.4 +/- 0.1 pmol small middle dotmin-1 small middle dotmg-1 protein in naïve mice, p <.05), and inhaled nitric oxide attenuated this increase in pulmonary inducible NO synthase activity (p <.05).
  
  
  CONCLUSIONS
  Exposure to inhaled nitric oxide early in the course of sepsis-induced acute lung injury is associated with reduced pulmonary leukocyte infiltration and less oxidative injury. Decreased lung inflammation and injury with inhaled nitric oxide is associated with decreased pulmonary inducible NO synthase activity. Therefore, inhaled NO may have greater clinical benefit if administered earlier in the natural history of acute lung injury in patients.
authors.affiliation: C. Burton Vascular Research Laboratory, Division of Respirology, London Health Sciences Center, University of Western Ontario, London, ON, Canada.
authors.forename: Habib M
authors.initials: HM
authors.lastname: Razavi
authors.forename: Robert
authors.initials: R
authors.lastname: Werhun
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Scott
authors.forename: Sean
authors.initials: S
authors.lastname: Weicker
authors.forename: Le Feng
authors.initials: le F
authors.lastname: Wang
authors.forename: David G
authors.initials: DG
authors.lastname: McCormack
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mehta
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D015237:Dinoprost / Q000031:analogs & derivatives*; D028441:F2-Isoprostanes / Q000032:analysis; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000032:analysis; D009195:Peroxidase / Q000032:analysis; D011897:Random Allocation; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications / Q000188:drug therapy*
chemical_list: D028441:F2-Isoprostanes; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D015237:Dinoprost; D009195:Peroxidase; D019001:Nitric Oxide Synthase