title: Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model.
abstract: 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.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555-0833, USA.
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhbaatar
authors.forename: Kazunori
authors.initials: K
authors.lastname: Murakami
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shimoda
authors.forename: Akio
authors.initials: A
authors.lastname: Mizutani
authors.forename: Roy
authors.initials: R
authors.lastname: McGuire
authors.forename: Frank
authors.initials: F
authors.lastname: Schmalstieg
authors.forename: Robert
authors.initials: R
authors.lastname: Cox
authors.forename: Hal
authors.initials: H
authors.lastname: Hawkins
authors.forename: Jeffery
authors.initials: J
authors.lastname: Jodoin
authors.forename: Steve
authors.initials: S
authors.lastname: Lee
authors.forename: Lillian
authors.initials: L
authors.lastname: Traber
authors.forename: David
authors.initials: D
authors.lastname: Herndon
authors.forename: Daniel
authors.initials: D
authors.lastname: Traber
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D007191:Indazoles; D012906:Smoke; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; C004479:pimagedine; C080122:7-nitroindazole