Combined neuronal and inducible nitric oxide synthase inhibition in ovine acute lung injury

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 Herndon, Perenlei Enkhbaatar

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

OBJECTIVE:: Acute 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. DESIGN:: Prospective, controlled, randomized trial. SETTING:: University research laboratory. SUBJECTS:: Eighteen chronically instrumented, adult, female sheep. INTERVENTIONS:: Following 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 RESULTS:: The 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. CONCLUSIONS:: The 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.

Original languageEnglish (US)
Pages (from-to)223-229
Number of pages7
JournalCritical Care Medicine
Volume37
Issue number1
DOIs
StatePublished - Jan 2009

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Keywords

  • 3-nitrotyrosine
  • Peroxynitrite
  • Poly(adenosine diphosphate ribose)
  • Smoke inhalation
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Lange, M., Connelly, R., Traber, D. L., Hamahata, A., Cox, R. A., Nakano, Y., Bansal, K., Esechie, A., Von Borzyskowski, S., Jonkam, C., Traber, L. D., Hawkins, H. K., Herndon, D., & Enkhbaatar, P. (2009). Combined neuronal and inducible nitric oxide synthase inhibition in ovine acute lung injury. Critical Care Medicine, 37(1), 223-229. https://doi.org/10.1097/CCM.0b013e3181926104