A specific neutrophil elastase inhibitor (ONO-5046·Na) attenuates LPS-induced acute lung inflammation in the hamster

Abstract

We have examined the effect of ONO-5046-Na, a synthetic specific inhibitor of neutrophil elastase, on lipopolysaccharide (LPS)-induced acute lung inflammation. Syrian golden hamsters were injected intraperitoneally with either 300 mg·kg-1 of ONO-5046·Na or saline, 30 min before and 1 h after intratracheal administration of 0.1 mg·kg-1 LPS. Animals were sacrificed 2 and 24 h later and the wet-to-dry lung weight ratio (W/D) was determined. Bronchoalveolar lavage (BAL) was performed, and tissue sections were examined histologically. The effect of ONO-5046·Na on migration of isolated neutrophils was determined. W/D was not significantly different at 2 h, but was increased at 24 h in the LPS-treated animals. This increase was attenuated in the LPS-treated animals injected with ONO-5046 Na. Analysis of BAL fluid revealed that both at 2 and 24 h after LPS administration the total cell number and neutrophil number, albumin concentration, and elastase-like activity were significantly lower in the LPS-treated animals injected with ONO-5046·Na than in those given LPS alone. Histological examination of the lungs of the animals treated with LPS alone showed intraalveolar haemorrhages and inflammatory cell infiltration 24 h after LPS administration, whereas the lungs of the LPS-treated ONO-5036·Na injected animals were only sparsely infiltrated by inflammatory cells, as indicated by the inflammation score. Although ONO-5046·Na had no effect on neutrophil migration in vitro; the present findings suggest that ONO-5046·Na attenuates LPS-induced acute lung inflammation by inhibiting neutrophil migration in vivo, and conversely that neutrophil elastase plays a considerable role in the pathogenesis of the acute lung inflammation induced by LPS.