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

Systemic inflammatory response syndrome (SIRS) is associated with excessive production of nitric oxide (NO•) and superoxide (O2−), forming peroxynitrite (ONOO−), which in turn, acts as a terminal mediator of cellular injury by producing cell necrosis and apoptosis. We examined the effect of the ONOO− decomposition catalyst WW-85 in a sheep model of acute lung injury (ALI) and septic shock. Eighteen sheep were operatively prepared and randomly allocated, either to the sham, control, or WW-85 group (n=6 each). Following a tracheotomy, ALI was produced in the control and WW-85 group by insufflation of four sets of 12 breaths of cotton smoke. Then, a 30 mL suspension of live Pseudomonas aeruginosa bacteria (containing 2–5×1011 cfu) 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 hrs and ventilated with 100% oxygen. WW-85 was administered 1 h post injury as bolus infusion (0.1 mg/kg), followed by a continuous infusion of 0.02 mg•kg−1•h−1 until the end of the 24-h experimental period. Compared to injured but untreated controls, WW-85-treated animals had significantly improved gas exchange, reductions in airway obstruction, shunt formation, lung myeloperoxidase-, lung malondialdehyde-, lung 3-nitrotyrosine concentrations, and plasma nitrate-to-nitrite (NOx) 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.