Molecular biological effects of selective neuronal nitric oxide synthase inhibition in ovine lung injury.
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.
Saunders
Fiona D
FD
Investigational Intensive Care Unit, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA. fiona.saunders@gmail.com
Westphal
Martin
M
Enkhbaatar
Perenlei
P
Wang
Jianpu
J
Pazdrak
Konrad
K
Nakano
Yoshimitsu
Y
Hamahata
Atsumori
A
Jonkam
Collette C
CC
Lange
Matthias
M
Connelly
Rhykka L
RL
Kulp
Gabriela A
GA
Cox
Robert A
RA
Hawkins
Hal K
HK
Schmalstieg
Frank C
FC
Horvath
Eszter
E
Szabo
Csaba
C
Traber
Lillian D
LD
Whorton
Elbert
E
Herndon
David N
DN
Traber
Daniel L
DL
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
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