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 per fusion flow. The vascular permeability was assessed by the capillary filtration coefficient (K-f,K-c) and the solvent-drag reflection coefficient (sigma(f)). PMA (13.3 mu g) increased vascular permeability was evidenced by an increase in K-f ,K- c from 0.18 +/- 0.02 to 0.92 +/- 0.14 mL/min/cmH(2)O/100 g and a decrease in sigma(f) to 0.35 +/- 0.01 as compared to control values of 0.69 +/- 0.06. The PMA-induced changes in K-f ,K- c and sigma(f) were dose-dependently attenuated by pretreatment with ONO-5046 (2-20 mg). We conclude that ONO-5046 can effectively attenuate the PMA-induced injury in the isolated blood-perfused dog lungs.