• Matthias Lange, Rhykka Connelly, Daniel L Traber, Atsumori Hamahata, Robert A Cox, Yoshimitsu Nakano, Kamna Bansal, Aimalohi Esechie, Sanna von Borzyskowski, Collette Jonkam, Lillian D Traber, Hal K Hawkins, David N Herndon, and Perenlei Enkhbaatar.
• Department of Anesthesiology, Investigational Intensive Care Unit, The University of Texas Medical Branch and Shriners Hospitals for Children, Galveston, TX, USA. lanm@gmx.de
• Crit. Care Med. 2009 Jan 1;37(1):223-9.

ObjectiveAcute lung injury with subsequent pneumonia and sepsis represents a major cause of morbidity and mortality in thermally injured patients. Production of nitric oxide by the neuronal and inducible nitric oxide synthase may be critically involved in the pathophysiology of the disease process at different time points, and thus specific inhibition at different times may represent an effective treatment regimen.DesignProspective, controlled, randomized trial.SettingUniversity research laboratory.SubjectsEighteen chronically instrumented, adult, female sheep.InterventionsFollowing baseline measurements, the animals were allocated to either sham-injured, nontreated controls (sham), injured, nontreated controls (control), or injured animals treated with continuous infusion of 7-nitroindazole, a specific neuronal nitric oxide synthase inhibitor, during the first 12 hrs postinjury and infusion of BBS-2, a specific inducible nitric oxide synthase inhibitor, during the next 12 hrs. Injury was induced by 48 breaths of cotton smoke and subsequent instillation of Pseudomonas aeruginosa into the lungs. All sheep were mechanically ventilated and fluid resuscitated for the entire duration of the 24-hr experiment.Measurements And Main ResultsThe injury induced severe pulmonary dysfunction, which was associated with increases in lung edema formation, airway obstruction, and vascular endothelial growth factor, 3-nitrotyrosine, and poly(adenosine diphosphate ribose) expression in lung tissue. The treatment reduced the degree of airway obstruction and improved pulmonary gas exchange, whereas the development of lung edema was not affected. The increases in lung tissue vascular endothelial growth factor, 3-nitrotyrosine, and poly(ribose) expression were attenuated by the treatment.ConclusionsThe combination of early neuronal nitric oxide synthase and delayed inducible nitric oxide synthase inhibition shows potential benefit in ovine acute lung injury by reducing nitrosative stress in the lung and limiting the degree of airway obstruction.

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