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

Departments of Anesthesiology and Pathology, University of Texas Medical Branch, and Shriners Burns Hospital, Galveston, Texas; and Departments of Medicinal Chemistry and Immunology, Berlex Biosciences, Richmond, California

Correspondence and requests for reprints should be addressed to Daniel L. Traber, Ph.D., Department of Anesthesiology, UTMB, 610 Texas Ave, Galveston, TX 77555. E-mail: dltraber{at}utmb.edu

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°C) under anesthesia. BBS-2 was provided by constant infusion at 100 µg/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.

Key Words: nitric oxide • acute respiratory distress syndrome • thermal injury

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