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Effects of neuronal nitric oxide synthase in ovine lung injury

Introduction

Excessive production of nitric oxide is a major factor contributing to acute lung injury and systemic inflammation after burn and smoke inhalation injury. We hypothesized that the use of 7-nitroindazole (7-NI), a selective nNOS inhibitor, blocks molecular mechanisms in this pathogenesis.

Methods

Eleven ewes were surgically instrumented and randomly allocated to either an injured untreated control group (40% total body surface area flame burn and 48 breaths of cotton smoke, n = 6), or an injury group treated with 7-NI (1 mg/kg/hour, n = 5).

Results

This insult was associated with systemic inflammation and oxidative stress, as evidenced by a 2.5-fold increase in plasma nitrite/nitrate (NOx) levels, as well as sixfold, twofold, threefold and twofold increases in IL-8, myeloperoxidase (MPO), malondialdehyde (MDA) and poly-ADP-ribose-polymerase (PARP) lung tissue concentrations, respectively. These molecular changes were linked to severe pulmonary derangements. Compared with untreated controls, 7-NI significantly reduced NOx plasma levels (8.4 ± 1 vs 26 ± 10 μmol/l) and decreased IL-8, MPO (3.9 ± 0.2 vs 5.8 ± 0.7 U/g tissue), MDA (2.7 ± 0.3 vs 6.6 ± 1.1 nmol/mg protein) and PARP lung tissue content (3.4 ± 0.7 vs 6.7 ± 0.7), thereby decreasing pulmonary obstruction (12.4 ± 2.2 vs 28.7 ± 5.2 obstruction score) and increasing the PaO2/FiO2 ratio (456 ± 40 vs 313 ± 56, each P < 0.05).

Conclusion

These data suggest that nNOS-derived NO plays a pivotal role in the pathophysiology of this double-hit injury and that selective nNOS inhibition may represent a useful approach to attenuate the degree of pulmonary damage.

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Saunders, F., Westphal, M., Enkhbaatar, P. et al. Effects of neuronal nitric oxide synthase in ovine lung injury. Crit Care 11, P16 (2007). https://doi.org/10.1186/cc5176

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Keywords

  • Nitric Oxide
  • Acute Lung Injury
  • Total Body Surface Area
  • Inhalation Injury
  • nNOS Inhibition