Combined neuronal and inducible nitric oxide synthase inhibition in ovine acute lung injury.
OBJECTIVE
Acute lung injury with subsequent pneumonia and sepsis represents a major cause of morbidity and mortality in thermally injured patients. Production of nitric oxide by the neuronal and inducible nitric oxide synthase may be critically involved in the pathophysiology of the disease process at different time points, and thus specific inhibition at different times may represent an effective treatment regimen.


METHODS
Prospective, controlled, randomized trial.


METHODS
University research laboratory.


METHODS
Eighteen chronically instrumented, adult, female sheep.


METHODS
Following baseline measurements, the animals were allocated to either sham-injured, nontreated controls (sham), injured, nontreated controls (control), or injured animals treated with continuous infusion of 7-nitroindazole, a specific neuronal nitric oxide synthase inhibitor, during the first 12 hrs postinjury and infusion of BBS-2, a specific inducible nitric oxide synthase inhibitor, during the next 12 hrs. Injury was induced by 48 breaths of cotton smoke and subsequent instillation of Pseudomonas aeruginosa into the lungs. All sheep were mechanically ventilated and fluid resuscitated for the entire duration of the 24-hr experiment.


RESULTS
The injury induced severe pulmonary dysfunction, which was associated with increases in lung edema formation, airway obstruction, and vascular endothelial growth factor, 3-nitrotyrosine, and poly(adenosine diphosphate ribose) expression in lung tissue. The treatment reduced the degree of airway obstruction and improved pulmonary gas exchange, whereas the development of lung edema was not affected. The increases in lung tissue vascular endothelial growth factor, 3-nitrotyrosine, and poly(ribose) expression were attenuated by the treatment.


CONCLUSIONS
The combination of early neuronal nitric oxide synthase and delayed inducible nitric oxide synthase inhibition shows potential benefit in ovine acute lung injury by reducing nitrosative stress in the lung and limiting the degree of airway obstruction.
Lange
Matthias
M
Department of Anesthesiology, Investigational Intensive Care Unit, The University of Texas Medical Branch and Shriners Hospitals for Children, Galveston, TX, USA. lanm@gmx.de
Connelly
Rhykka
R
Traber
Daniel L
DL
Hamahata
Atsumori
A
Cox
Robert A
RA
Nakano
Yoshimitsu
Y
Bansal
Kamna
K
Esechie
Aimalohi
A
von Borzyskowski
Sanna
S
Jonkam
Collette
C
Traber
Lillian D
LD
Hawkins
Hal K
HK
Herndon
David N
DN
Enkhbaatar
Perenlei
P
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D007191:Indazoles / Q000627:therapeutic use*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012756:Sheep
D004791:Enzyme Inhibitors; D007093:Imidazoles; D007191:Indazoles; C487929:N-((1,3-benzodioxol-5-yl)methyl)-1-(2-(1H-imidazol-1-yl)pyrimidin-4-yl)-4-(methoxycarbonyl)piperazine-2-acetamide; D010879:Piperazines; D011743:Pyrimidines; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C080122:7-nitroindazole