Neuronal nitric oxide synthase inhibition attenuates cardiopulmonary dysfunctions after combined burn and smoke inhalation injury in sheep

Martin Westphal, Perenlei Enkhbaatar, Frank C. Schmalstieg, Gabriela A. Kulp, Lillian D. Traber, Naoki Morita, Robert A. Cox, Hal K. Hawkins, Beena B. Westphal-Varghese, Helen E. Rudloff, Dirk M. Maybauer, Marc O. Maybauer, Ann S. Burke, Kazunori Murakami, Fiona Saunders, Eszter M. Horvath, Csaba Szabo, Daniel L. Traber

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

OBJECTIVE: We hypothesized that nitric oxide derived from the neuronal nitric oxide synthase (NOS) is responsible for much of the injury resulting from skin burn and smoke inhalation. Therefore, we aimed to examine the effects of selective neuronal NOS inhibition on cardiopulmonary functions and cellular injury in sheep with acute respiratory distress syndrome secondary to combined burn and smoke inhalation injury. DESIGN: Prospective, randomized, controlled laboratory experiment. SETTING: Investigational intensive care unit. SUBJECTS: A total of 22 chronically instrumented adult ewes. INTERVENTIONS: Sheep were randomly assigned to either healthy controls (sham), injured controls (40% third-degree flame burn; 48 breaths of cotton smoke), or an injury group treated with the specific neuronal NOS inhibitor 7-nitroindazole (1 mg·kg·hr) from 1 hr postinjury to the end of the 48-hr study period. Hypoxic pulmonary vasoconstriction was assessed as decrease in left pulmonary blood flow in response to single-lung hypoxic challenges (100% nitrogen) at baseline, 24 hrs, and 48 hrs. MEASUREMENTS AND MAIN RESULTS: The combination injury contributed to a ∼90% loss of hypoxic pulmonary vasoconstriction and was associated with significant pulmonary shunting and death of one animal. The increase in nitrate/nitrite plasma levels in injured controls (12 hrs: 17 ± 2 vs. 6 ± 1 μM in sham animals; p < .001) was linked to increases in inducible NOS messenger RNA and 3-nitrotyrosine formation in lung tissue (48 hrs: 22 ± 1 vs. 0.8 ± 0.3 nM in sham animals; p < .001). 7-Nitroindazole treatment prevented the injury-associated changes in inducible NOS messenger RNA, nitrate/nitrite, and 3-nitrotyrosine, thereby attenuating the loss of hypoxic pulmonary vasoconstriction and improving gas exchange. In addition, 7-nitroindazole decreased lung tissue concentrations of hemoxygenase-1 and ameliorated myocardial depression, airway obstruction, pulmonary edema, ventilatory pressures, and histopathologic changes seen in injured controls. CONCLUSIONS: The present study provides evidence that neuronal NOS-derived nitric oxide plays a pivotal role in the pathogenesis of acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.

Original languageEnglish (US)
Pages (from-to)1196-1204
Number of pages9
JournalCritical care medicine
Volume36
Issue number4
DOIs
StatePublished - Apr 2008

Keywords

  • Acute respiratory distress syndrome
  • Hypoxic pulmonary vasoconstriction
  • Nitric oxide synthase
  • Peroxynitrite
  • Sheep
  • Systemic inflammation

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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    Westphal, M., Enkhbaatar, P., Schmalstieg, F. C., Kulp, G. A., Traber, L. D., Morita, N., Cox, R. A., Hawkins, H. K., Westphal-Varghese, B. B., Rudloff, H. E., Maybauer, D. M., Maybauer, M. O., Burke, A. S., Murakami, K., Saunders, F., Horvath, E. M., Szabo, C., & Traber, D. L. (2008). Neuronal nitric oxide synthase inhibition attenuates cardiopulmonary dysfunctions after combined burn and smoke inhalation injury in sheep. Critical care medicine, 36(4), 1196-1204. https://doi.org/10.1097/CCM.0b013e31816a1a0c