Sivelestat, a specific neutrophil elastase inhibitor, prevented phorbol myristate acetate-induced acute lung injury in conscious rabbits

The in vivo contribution of neutrophil elastase (NE) in phorbol myristate acetate (PMA)-induced acute lung injury has so far been unclear. This study examined the role of NE in PMA-induced acute lung injury in conscious rabbits, using a specific NE inhibitor, sivelestat sodium hydrate (Sivelestat). A single bolus injection of PMA (40 μg/kg) caused acute lung injury as indicated by an increase in protein concentration and hemorrhage in bronchoalveolar lavage fluid (BALF) 4 h after PMA injection. These changes were associated with mild decrease in arterial oxygen pressure and peripheral white blood cell and platelet. When continuously infused starting 1 h before and ending 4 h post-PMA injection, Sivelestat at 3-30 mg/kg/h that are able to inhibit rabbit NE activity by 60-90%, dose-dependently attenuated both PMA-induced hemorrhagic pneumonitis and the increase in protein concentration in BALF without affecting myeloperoxidase activity in the lung. Histopathological study indicated that sivelestat (30 mg/kg/h) markedly attenuated lung histopathological changes, alveolar hemorrhage and white blood cells migration with evidence of inhibition of NE activity in BALF. These results suggest that NE plays a significant role in PMA-induced acute lung injury and further supports the importance of this enzyme in acute lung injury.