The peroxynitrite catalyst WW-85 improves pulmonary function in ovine septic shock

Dirk M. Maybauer, Marc O. Maybauer, Csaba Szabó, Robert A. Cox, Martin Westphal, Levente Kiss, Eszter M. Horvath, Lillian D. Traber, Hal K. Hawkins, Andrew L. Salzman, Garry J. Southan, David N. Herndon, Daniel L. Traber

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Systemic inflammatory response syndrome is associated with excessive production of nitric oxide (NO•) and superoxide (O2), forming peroxynitrite, which in turn, acts as a terminal mediator of cellular injury by producing cell necrosis and apoptosis. We examined the effect of the peroxynitrite decomposition catalyst, WW-85, in a sheep model of acute lung injury and septic shock. Eighteen sheep were operatively prepared and randomly allocated to the sham, control, or WW-85 group (n = 6 each). After a tracheotomy, acute lung injury was produced in the control and WW-85 groups by insufflation of four sets of 12 breaths of cotton smoke. Then, a 30-mL suspension of live Pseudomonas aeruginosa bacteria (containing 2 - 5 × 10 11 colony-forming units) was instilled into the lungs according to an established protocol. The sham group received only the vehicle (30 mL saline). The sheep were studied in awake state for 24 h and ventilated with 100% oxygen. WW-85 was administered 1 h after injury as bolus infusion (0.1 mg/kg), followed by a continuous infusion of 0.02 mgkg -1h -1 until the end of the 24-h experimental period. Compared with injured but untreated controls, WW-85-treated animals had significantly improved gas exchange, reductions in airway obstruction, shunt formation, lung myeloperoxidase concentrations, lung malondialdehyde concentrations, lung 3-nitrotyrosine concentrations, and plasma nitrate-to-nitrite levels. Animals treated with WW-85 exhibited less microvascular leakage and improvements in pulmonary function. These results provide evidence that blockade of the nitric oxide-peroxynitrite pathway improves disturbances from septic shock, as demonstrated in a clinically relevant ovine experimental model.

Original languageEnglish (US)
Pages (from-to)148-155
Number of pages8
JournalShock
Volume35
Issue number2
DOIs
StatePublished - Feb 1 2011

Keywords

  • ARDS
  • Airway obstruction
  • nitric oxide
  • nitrotyrosine
  • smoke inhalation

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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    Maybauer, D. M., Maybauer, M. O., Szabó, C., Cox, R. A., Westphal, M., Kiss, L., Horvath, E. M., Traber, L. D., Hawkins, H. K., Salzman, A. L., Southan, G. J., Herndon, D. N., & Traber, D. L. (2011). The peroxynitrite catalyst WW-85 improves pulmonary function in ovine septic shock. Shock, 35(2), 148-155. https://doi.org/10.1097/SHK.0b013e3181eb4556