EFFECT OF ONO-5046, A SPECIFIC NEUTROPHIL ELASTASE INHIBITOR, ON THE PHORBOL MYRISTATE ACETATE-INDUCED INJURY IN ISOLATED DOG LUNG

Phorbol myristate acetate (PMA) activates neutrophils and causes acute lung injury. We determined the effect of ONO-5046, a specific neutrophil elastase inhibitor, on the increase in microvascular permeability induced by PMA in isolated dog lung perfused with autologous blood at a constant perfusion flow. The vascular permeability was assessed by the capillary filtration coefficient (Kf,c) and the solvent-drag reflection coefficient (sigmaf). PMA (13.3mug) increased vascular permeability, as evidenced by an increase in Kf,c from 0.18 +/- 0.02 to 0.92 +/- 0.14mL/min/cmH2O/100g and a decrease in sigmaf to 0.35 +/- 0.01 as compared to control values of 0.69 +/- 0.06. The PMA-induced changes in Kf,c and sigmaf were dose-dependently attenuated by pretreatment with ONO-5046 (2-20mg). We conclude that ONO-5046 can effectively attenuate the PMA-induced injury in the isolated blood-perfused dog lungs.