The Inducible Nitric Oxide Synthase Inhibitor BBS-2 Prevents Acute Lung Injury in Sheep after Burn and Smoke Inhalation Injury

• Published in: American journal of respiratory and critical care medicine 2003-04, Vol.167 (7), p.1021-1026
• Main Authors: Enkhbaatar, Perenlei, Murakami, Kazunori, Shimoda, Katsumi, Mizutani, Akio, Traber, Lillian, Phillips, Gary B, Parkinson, John F, Cox, Robert, Hawkins, Hal, Herndon, David, Traber, Daniel
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Pressure - drug effects; Body Surface Area; Burns - complications; Burns - drug therapy; Disease Models, Animal; Enzyme Inhibitors - therapeutic use; Extravascular Lung Water - drug effects; Female; Heart Rate - drug effects; Lymph Nodes - drug effects; Medical sciences; Models, Cardiovascular; Nitrates - blood; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - therapeutic use; Nitric Oxide Synthase Type II; Nitrites - blood; Pneumology; Proteins - therapeutic use; Pulmonary Circulation - drug effects; Pulmonary Gas Exchange - drug effects; Respiratory Distress Syndrome, Adult - blood; Respiratory Distress Syndrome, Adult - etiology; Respiratory Distress Syndrome, Adult - prevention & control; Respiratory system : syndromes and miscellaneous diseases; Severity of Illness Index; Sheep; Smoke Inhalation Injury - blood; Smoke Inhalation Injury - complications; Smoke Inhalation Injury - drug therapy; Time Factors; Treatment Outcome
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200209-1031PP

In this study we examined the role of inducible nitric oxide synthase (iNOS) in acute respiratory distress syndrome (ARDS) in sheep with severe combined burn and smoke inhalation injury. BBS-2, a potent and highly selective iNOS dimerization inhibitor, was used to exclude effects on the endothelial and neuronal NOS isoforms. Seven days after surgical recovery, sheep were given a burn (40% of total body surface, 3rd degree) and insufflated with cotton smoke (48 breaths, < 40 degrees C) under anesthesia. BBS-2 was provided by constant infusion at 100 microg/kg/hour, beginning 1 hour after injury. During 48 hours, control sheep developed multiple signs of ARDS. These included decreased pulmonary gas exchange, increased pulmonary edema, abnormal lung compliance, and extensive airway obstruction. These pathologies were associated with a large increase in tracheal blood flow and elevated plasma NO2-/NO3- (NOx) levels. These variables were all stable in sham animals. Treatment of injured sheep with BBS-2 attenuated the increases in tracheal blood flow and plasma NOx levels, and significantly attenuated all the pulmonary pathologies that were noted. The results provide definitive evidence that iNOS is a key mediator of pulmonary pathology in sheep with ARDS resulting from combined burn and smoke inhalation injury.