Effect of poly(ADP ribose) synthetase inhibition on burn and smoke inhalation injury in sheep

1 Departments of Anesthesiology, Pathology, and Pediatrics, The University of Texas Medical Branch, Shriners Burns Hospital, Galveston, Texas 77555-0833; and 2 Inotek Pharmaceuticals, Beverly, Massachusetts 01915 Submitted 20 September 2002 ; accepted in final form 28 February 2003 We investigated the role of the nuclear enzyme poly (ADP ribose) synthetase (PARS) in the pathogenesis of combined burn and smoke inhalation (burn/smoke) injury in an ovine model. Eighteen sheep were operatively prepared for chronic study. PARS inhibition was achieved by treatment with a novel and selective PARS inhibitor INO-1001. The PARS inhibitor attenuated 1 ) lung edema formation, 2 ) deterioration of gas exchange, 3 ) changes in airway blood flow, 4 ) changes in airway pressure, 5 ) lung histological injury, and 6 ) systemic vascular leakage. Lipid oxidation and plasma nitrite/nitrate (stable breakdown products of nitric oxide) levels were suppressed with the use of INO-1001. We conclude that PARS inhibition attenuates various aspects of the pathophysiological response in a clinically relevant experimental model of burn/smoke inhalation injury. acute respiratory distress syndrome; lung lymphatic; nitric oxide Address for reprint requests and other correspondence: D. L. Traber, Investigational Intensive Care Unit, Dept. of Anesthesiology, The Univ. of Texas Medical Branch, 610 Texas Ave., Galveston, TX 77555-0833 (E-mail: dltraber{at}utmb.edu ).