title: The peroxynitrite catalyst WW-85 improves pulmonary function in ovine septic shock.
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 × 10¹¹ 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 mg·kg⁻¹·h⁻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.
authors.affiliation: Departments of Anesthesiology, Pathology, and Surgery, Investigational Intensive Care Unit, The University of Texas Medical Branch and Shriners Burns Hospital for Children, Galveston, Texas, USA. dmmaybau@utmb.edu
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Maybauer
authors.forename: Marc O
authors.initials: MO
authors.lastname: Maybauer
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Martin
authors.initials: M
authors.lastname: Westphal
authors.forename: Levente
authors.initials: L
authors.lastname: Kiss
authors.forename: Eszter M
authors.initials: EM
authors.lastname: Horvath
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Hal K
authors.initials: HK
authors.lastname: Hawkins
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Salzman
authors.forename: Garry J
authors.initials: GJ
authors.lastname: Southan
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002384:Catalysis; D004195:Disease Models, Animal; D005260:Female; D008168:Lung / Q000378:metabolism / Q000503:physiopathology; D008315:Malondialdehyde / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000494:pharmacology; D011659:Pulmonary Gas Exchange; D012129:Respiratory Function Tests; D012756:Sheep; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
chemical_list: D009566:Nitrates; C506898:WW85 compound; D030421:Peroxynitrous Acid; D008315:Malondialdehyde; D009195:Peroxidase