Am. J. Respir. Crit. Care Med., Volume 161, Number 6, June 2000, 2013-2018

Delayed Neutrophil Elastase Inhibition Prevents Subsequent Progression of Acute Lung Injury Induced by Endotoxin Inhalation in Hamsters

KAZUHITO KAWABATA, TETSUYA HAGIO, SHIGERU MATSUMOTO, SHINTARO NAKAO, SHINICHIRO ORITA, YOSHIYA AZE, and HIROYUKI OHNO

Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan; and Fukui Safety Institute, Ono Pharmaceutical Co., Ltd., Fukui, Japan

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 specific NE inhibitor, sivelestat sodium hydrate (sivelestat), on ALI induced by endotoxin (ET) inhalation in hamsters. Inhalation of ET (300 µg/ml, 30 min) in conscious hamsters increased inflammatory cell count, protein concentration, and hemorrhage in bronchoalveolar lavage fluid (BALF) that peaked 24 h after ET inhalation. These changes were significant 2 h after ET inhalation 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) dose-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 progression of lung inflammation such as alveolar neutrophil infiltration and hemorrhage. In contrast, dexamethasone (3 mg/kg, intravenously) was not effective in this model when administered 2 h after ET inhalation, although it was highly effective when applied before ET. We conclude that delayed inhibition of NE activity with sivelestat prevents subsequent progression of ALI in hamsters after ET inhalation. Thus NE may play an important role in the progression of ALI.

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