title: Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury.
abstract: During acute lung injury, nitric oxide (NO) exerts cytotoxic effects by reacting with superoxide radicals, yielding the reactive nitrogen species peroxynitrite (ONOO(-)). ONOO(-) exerts cytotoxic effects, among others, by nitrating/nitrosating proteins and lipids, by activating the nuclear repair enzyme poly(ADP-ribose) polymerase and inducing VEGF. Here we tested the effect of the ONOO(-) decomposition catalyst INO-4885 on the development of lung injury in chronically instrumented sheep with combined burn and smoke inhalation injury. The animals were randomized to a sham-injured group (n = 7), an injured control group [48 breaths of cotton smoke, 3rd-degree burn of 40% total body surface area (n = 7)], or an injured group treated with INO-4885 (n = 6). All sheep were mechanically ventilated and fluid-resuscitated according to the Parkland formula. The injury-related increases in the abundance of 3-nitrotyrosine, a marker of protein nitration by ONOO(-), were prevented by INO-4885, providing evidence for the neutralization of ONOO(-) action by the compound. Burn and smoke injury induced a significant drop in arterial Po(2)-to-inspired O(2) fraction ratio and significant increases in pulmonary shunt fraction, lung lymph flow, lung wet-to-dry weight ratio, and ventilatory pressures; all these changes were significantly attenuated by INO-4885 treatment. In addition, the increases in IL-8, VEGF, and poly(ADP-ribose) in lung tissue were significantly attenuated by the ONOO(-) decomposition catalyst. In conclusion, the current study suggests that ONOO(-) plays a crucial role in the pathogenesis of pulmonary microvascular hyperpermeability and pulmonary dysfunction following burn and smoke inhalation injury in sheep. Administration of an ONOO(-) decomposition catalyst may represent a potential treatment option for this injury.
authors.affiliation: Department of Anesthesiology, Investigational Intensive Care Unit, The Univ. of Texas Medical Branch, Shriners Hospitals for Children, Galveston, 77550, USA. lanm@gmx.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Lange
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: Rhykka
authors.initials: R
authors.lastname: Connelly
authors.forename: Eszter
authors.initials: E
authors.lastname: Horvath
authors.forename: Atsumori
authors.initials: A
authors.lastname: Hamahata
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Aimalohi
authors.initials: A
authors.lastname: Esechie
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Nakano
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D000818:Animals; D002056:Burns / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects; D002384:Catalysis; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008665:Metalloporphyrins / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism* / Q000633:toxicity; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C539253:(5,10,15,20-tetrakis(N-(benzyl-4'-carboxylate)-2-pyridinium)-21H,23H-porphine)iron(III); D016209:Interleukin-8; D008665:Metalloporphyrins; D042461:Vascular Endothelial Growth Factor A; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases