OPC-6535, A SUPEROXIDE ANION PRODUCTION INHIBITOR, ATTENUATES ACUTE LUNG INJURY

A large body of evidence has demonstrated that inhibition of the neutr ophil's oxidant burst attenuates sepsis-induced acute lung injury. The present study sought to evaluate the ability of OPC-6535, a superoxid e anion production inhibitor, to attenuate sepsis-induced acute lung i njury. Four groups of swine were anesthetized, ventilated, and studied for 5 hr. Following surgical preparation, control (n = 10) and OPC-co ntrol (n = 2) animals received a 1-hr infusion of sterile saline. Seps is was induced with a 1-hr intravenous infusion of live Pseudomonas ae ruginosa. Untreated septic animals (n = 10) received no treatment. Ani mals treated with OPC-6535 (n = 6) received a 1 mg/kg bolus of OPC-653 5 15 min prior to initiation of the bacterial infusion. Changes in sys temic and pulmonary hemodynamics, arterial oxygen tension, bronchoalve olar lavage protein and neutrophil content, neutrophil integrin expres sion, neutrophil oxidant burst, and lung myeloperoxidase content were used as outcome measures. Treatment with OPC-6535 significantly reduce d acute lung injury, as indicated by improved bronchoalveolar lavage p rotein and neutrophil content, resulting in a significant improvement in arterial oxygenation. Treatment with OPC-6535 failed to prevent the development of pulmonary hypertension and systemic hypotension. Neutr ophils from animals with both treated and untreated sepsis exhibited s ignificant up-regulation of CD18 and production of increased levels of oxidants, indicating significant activation when compared to neutroph ils from control animals. Although animals treated with OPC-6535 produ ced 25% less superoxide anion than untreated septic animals, this decr ease was not statistically significant. Treatment of animals with OPC- 6535 prior to the onset of sepsis produced significant protection agai nst acute lung injury but failed to attenuate hemodynamic derangements associated with sepsis. (C) 1997 Academic Press.