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INFLAMMATION, CYTOKINES, AND TEMPERATURE REGULATION

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

¹Department of Anesthesiology, Pathology, Pediatrics, and Surgery, University Texas Medical Branch, and ²Shriners 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 10¹¹ 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, 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_O2/FI_O2; where Pa_O2 is arterial P_O2 and FI_O2 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

This article has been cited by other articles:

				B. Hauser, H. Bracht, M. Matejovic, P. Radermacher, and B. Venkatesh Nitric Oxide Synthase Inhibition in Sepsis? Lessons Learned from Large-Animal Studies Anesth. Analg., August 1, 2005; 101(2): 488 - 498. [Abstract] [Full Text] [PDF]