Delayed neutrophil elastase inhibition prevents subsequent progression of acute lung injury induced by endotoxin inhalation in hamsters

To define the role of neutrophil elastase (NE) in the progression of acute lung injury (ALI), we examined the effects of post-treatment with a specifi c NE inhibitor, sivelestat sodium hydrate (sivelestat), on ALI induced by e ndotoxin (ET) inhalation in hamsters. Inhalation of ET (300 mu g/ml, 30 min ) in conscious hamsters increased inflammatory cell count, protein concentr ation, and hemorrhage in bronchoalveolar lavage fluid (BALF) that peaked 24 h after ET inhalation. These changes were significant 2 h after ET inhalat ion and paralleled the increase in NE activity in BALF. When intravenously infused from 2 to 24 h post-ET inhalation, sivelestat (0.03 to 3 mg/kg/h) d ose-dependently attenuated changes in these BALF parameters at 24 h post-ET inhalation in a manner dependent on the inhibition of NE activity in BALF. Histopathological analysis also indicated that sivelestat prevented the pr ogression of lung inflammation such as alveolar neutrophil infiltration and hemorrhage. In contrast, dexamethasone (3 mg/kg, intravenously) was not ef fective in this model when administered 2 h after ET inhalation, although i t was highly effective when applied before ET. We conclude that delayed inh ibition of NE activity with sivelestat prevents subsequent progression of A LI in hamsters after ET inhalation. Thus NE may play an important role in t he progression of ALI.