Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 285; no. 2; pp. 366 - R372
• Main Authors: Enkhbaatar, Perenlei, Murakami, Kazunori, Shimoda, Katsumi, Mizutani, Akio, McGuire, Roy, Schmalstieg, Frank, Cox, Robert, Hawkins, Hal, Jodoin, Jeffery, Lee, Steve, Traber, Lillian, Herndon, David, Traber, Daniel
• Format: Journal Article
• Language: English
• Published: United States 01.08.2003
• Subjects: Acute Disease; Animals; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Guanidines - pharmacology; Indazoles - pharmacology; Indazoles - therapeutic use; Lung Diseases - chemically induced; Lung Diseases - drug therapy; Lung Diseases - enzymology; Lung Diseases - pathology; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; omega-N-Methylarginine - pharmacology; Pneumonia, Bacterial - drug therapy; Sheep, Domestic; Smoke - adverse effects
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00148.2003

1 Department of Anesthesiology, Pathology, Pediatrics, and Surgery, University Texas Medical Branch, and 2 Shriners Hospital for Children, Burns Unit, Galveston, Texas 77555-0833 Submitted 25 March 2003 ; accepted in final form 2 May 2003 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°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% O 2 . Continuous infusion of 7-nitroindazole (7-NI), an nNOS inhibitor, N G -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 (Pa O 2 /F I O 2 ; where Pa O 2 is arterial P O 2 and F I O 2 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. acute respiratory distress syndrome; smoke inhalation; pneumonia Address for reprint requests and other correspondence: D. L. Traber, Dept. of Anesthesiology, Univ. of Texas Medical Branch, 301 Univ. Boulevard, Galveston, TX 77555-0833 (E-mail: dltraber{at}utmb.edu ).