Role of neutrophil elastase in ozone-induced airway responses in guinea-pigs

Ozone-induced airway hyperresponsiveness occurs concurrently with neutrophi lic inflammation and epithelial injury in various species including humans. The mechanism of neutrophil-induced airway hyperresponsiveness, however, h as not yet been fully clarified. Neutrophil elastase (NE) is a multipotent protease released from activated neutrophils, which may play a role in ozon e-induced airway hyperresponsiveness, In order to address this issue, the e ffects of ONO-5046, a specific NE inhibitor, were investigated in ozone-exp osed guinea-pigs. Awake animals were exposed to ozone at 3 parts per million for 2 h, airway responsiveness to acetylcholine (ACh) measured and examination of bronchoal veolar lavage fluid (BALF) performed. Ozone exposure increased airway responsiveness to both inhaled and intraven ous ACh, the concentration of NE in BALE and the number of neutrophils and airway epithelial cells in BALF. Although pretreatment with ONO-5046 (200 m g.kg(-1), i.p.) had no effect on these changes immediately after the exposu re, it significantly inhibited airway hyperresponsiveness to inhaled ACh, w hilst decreasing the number of neutrophils and epithelial cells in BALE 3-5 h after the exposure. In contrast, ONO-5046 showed no significant effect o n airway hyperresponsiveness to intravenous ACh at any time, These results suggest that neutrophil elastase contributes to ozone-induced airway hyperresponsiveness developing during the hours after exposure, pre sumably by means of inducing epithelial injury.