• Fiona D Saunders, Martin Westphal, Perenlei Enkhbaatar, Jianpu Wang, Konrad Pazdrak, Yoshimitsu Nakano, Atsumori Hamahata, Collette C Jonkam, Matthias Lange, Rhykka L Connelly, Gabriela A Kulp, Robert A Cox, Hal K Hawkins, Frank C Schmalstieg, Eszter Horvath, Csaba Szabo, Lillian D Traber, Elbert Whorton, David N Herndon, and Daniel L Traber.
• Investigational Intensive Care Unit, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA. fiona.saunders@gmail.com
• Am. J. Physiol. Lung Cell Mol. Physiol. 2010 Mar 1;298(3):L427-36.

AbstractNeuronal nitric oxide synthase is critically involved in the pathogenesis of acute lung injury resulting from combined burn and smoke inhalation injury. We hypothesized that 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, blocks central molecular mechanisms involved in the pathophysiology of this double-hit insult. Twenty-five adult ewes were surgically prepared and randomly allocated to 1) an uninjured, untreated sham group (n = 7), 2) an injured control group with no treatment (n = 7), 3) an injury group treated with 7-nitroindazole from 1-h postinjury to the remainder of the 24-h study period (n = 7), or 4) a sham-operated group subjected only to 7-nitroindazole to judge the effects in health. The combination injury was associated with twofold increased activity of neuronal nitric oxide synthase and oxidative/nitrosative stress, as indicated by significant increases in plasma nitrate/nitrite concentrations, 3-nitrotyrosine (an indicator of peroxynitrite formation), and malondialdehyde lung tissue content. The presence of systemic inflammation was evidenced by twofold, sixfold, and threefold increases in poly(ADP-ribose) polymerase, IL-8, and myeloperoxidase lung tissue concentrations, respectively (each P < 0.05 vs. sham). These molecular changes were linked to tissue damage, airway obstruction, and pulmonary shunting with deteriorated gas exchange. 7-Nitroindazole blocked, or at least attenuated, all these pathological changes. Our findings suggest 1) that nitric oxide formation derived from increased neuronal nitric oxide synthase activity represents a pivotal reactive agent in the patho-physiology of combined burn and smoke inhalation injury and 2) that selective neuronal nitric oxide synthase inhibition represents a goal-directed approach to attenuate the degree of injury.

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