Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model.
Nitric oxide (NO) has been shown to play a major role in acute lung injury (ALI) after smoke inhalation. In the present study, we developed an ovine sepsis model, created by exposing sheep to smoke inhalation followed by instillation of bacteria into the airway, that mimics human sepsis and pneumonia. We hypothesized that the inhibition of neuronal NO synthase (nNOS) might be beneficial in treating ALI associated with this model. Female sheep (n = 26) were surgically prepared for the study and given a tracheostomy. This was followed by insufflation of 48 breaths of cotton smoke (40 degrees C) into the airway of each animal and subsequent instillation of live Pseudomonas aeruginosa [5 x 10(11) colony forming units (CFU)] into each sheep's lung. All sheep were mechanically ventilated using 100% O2. Continuous infusion of 7-nitroindazole (7-NI), an nNOS inhibitor, NG-monomethyl-l-arginine (l-NMMA), a nonspecific NOS inhibitor, or aminoguanidine (AG), an inducible NOS inhibitor, was started 1 h after insult. The administration of 7-NI improved pulmonary gas exchange (PaO2/FiO2; where PaO2 is arterial PO2 and FiO2 is fractional inspired oxygen concentration) and pulmonary shunt fraction and attenuated the increase in lung wet-to-dry weight ratio seen in the nontreated sheep. Histologically, 7-NI prevented airway obstruction. The increase in airway blood flow after injury in the nontreated group was significantly inhibited by 7-NI. The increase in plasma concentration of nitrate and nitrite (NOx) was inhibited by 7-NI as well. Posttreatment with l-NMMA improved the pulmonary gas exchange, but AG did not. The results of the present study show that nNOS may be involved in the pathogenesis of ALI after smoke inhalation injury followed by bacterial instillation in the airway.
Enkhbaatar
Perenlei
P
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555-0833, USA.
Murakami
Kazunori
K
Shimoda
Katsumi
K
Mizutani
Akio
A
McGuire
Roy
R
Schmalstieg
Frank
F
Cox
Robert
R
Hawkins
Hal
H
Jodoin
Jeffery
J
Lee
Steve
S
Traber
Lillian
L
Herndon
David
D
Traber
Daniel
D
D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000188:drug therapy; D034561:Sheep, Domestic; D012906:Smoke / Q000009:adverse effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006146:Guanidines; D007191:Indazoles; D012906:Smoke; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; C080122:7-nitroindazole