title: Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury.
abstract: Neuronal nitric oxide synthase is critically involved in the pathogenesis of acute lung injury resulting from combined burn and smoke inhalation injury. We hypothesized that 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, blocks central molecular mechanisms involved in the pathophysiology of this double-hit insult. Twenty-five adult ewes were surgically prepared and randomly allocated to 1) an uninjured, untreated sham group (n = 7), 2) an injured control group with no treatment (n = 7), 3) an injury group treated with 7-nitroindazole from 1-h postinjury to the remainder of the 24-h study period (n = 7), or 4) a sham-operated group subjected only to 7-nitroindazole to judge the effects in health. The combination injury was associated with twofold increased activity of neuronal nitric oxide synthase and oxidative/nitrosative stress, as indicated by significant increases in plasma nitrate/nitrite concentrations, 3-nitrotyrosine (an indicator of peroxynitrite formation), and malondialdehyde lung tissue content. The presence of systemic inflammation was evidenced by twofold, sixfold, and threefold increases in poly(ADP-ribose) polymerase, IL-8, and myeloperoxidase lung tissue concentrations, respectively (each P < 0.05 vs. sham). These molecular changes were linked to tissue damage, airway obstruction, and pulmonary shunting with deteriorated gas exchange. 7-Nitroindazole blocked, or at least attenuated, all these pathological changes. Our findings suggest 1) that nitric oxide formation derived from increased neuronal nitric oxide synthase activity represents a pivotal reactive agent in the patho-physiology of combined burn and smoke inhalation injury and 2) that selective neuronal nitric oxide synthase inhibition represents a goal-directed approach to attenuate the degree of injury.
authors: Investigational Intensive Care Unit, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA. fiona.saunders@gmail.com
authors: Fiona D
authors: FD
authors: Saunders
authors: Martin
authors: M
authors: Westphal
authors: Perenlei
authors: P
authors: Enkhbaatar
authors: Jianpu
authors: J
authors: Wang
authors: Konrad
authors: K
authors: Pazdrak
authors: Yoshimitsu
authors: Y
authors: Nakano
authors: Atsumori
authors: A
authors: Hamahata
authors: Collette C
authors: CC
authors: Jonkam
authors: Matthias
authors: M
authors: Lange
authors: Rhykka L
authors: RL
authors: Connelly
authors: Gabriela A
authors: GA
authors: Kulp
authors: Robert A
authors: RA
authors: Cox
authors: Hal K
authors: HK
authors: Hawkins
authors: Frank C
authors: FC
authors: Schmalstieg
authors: Eszter
authors: E
authors: Horvath
authors: Csaba
authors: C
authors: Szabo
authors: Lillian D
authors: LD
authors: Traber
authors: Elbert
authors: E
authors: Whorton
authors: David N
authors: DN
authors: Herndon
authors: Daniel L
authors: DL
authors: Traber
mesh_terms: D000402:Airway Obstruction / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D055370:Lung Injury / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D008315:Malondialdehyde / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011312:Pressure; D012039:Regional Blood Flow / Q000187:drug effects; D012129:Respiratory Function Tests; D012756:Sheep; D016019:Survival Analysis; D014132:Trachea / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D007191:Indazoles; D016209:Interleukin-8; D009566:Nitrates; D009573:Nitrites; D051996:Transcription Factor RelA; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D009195:Peroxidase; D052248:Nitric Oxide Synthase Type I; D011065:Poly(ADP-ribose) Polymerases; C080122:7-nitroindazole