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

Ozone-induced airway hyperresponsiveness occurs concurrently with neutrophilic inflammation and epithelial injury in various species including humans. The mechanism of neutrophil-induced airway hyperresponsiveness, however, has not yet been fully clarified. Neutrophil elastase (NE) is a multipotent protease released from activated neutrophils, which may play a role in ozone-induced airway hyperresponsiveness. In order to address this issue, the effects of ONO-5046, a specific NE inhibitor, were investigated in ozone-exposed 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 bronchoalveolar lavage fluid (BALF) performed. Ozone exposure increased airway responsiveness to both inhaled and intravenous ACh, the concentration of NE in BALF and the number of neutrophils and airway epithelial cells in BALF. Although pretreatment with ONO-5046 (200 mg x kg(-1), i.p.) had no effect on these changes immediately after the exposure, it significantly inhibited airway hyperresponsiveness to inhaled ACh, whilst decreasing the number of neutrophils and epithelial cells in BALF 3-5 h after the exposure. In contrast, ONO-5046 showed no significant effect on 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, presumably by means of inducing epithelial injury.

This article has been cited by other articles:

				E. Kolaczkowska, W. Grzybek, N. van Rooijen, H. Piccard, B. Plytycz, B. Arnold, and G. Opdenakker Neutrophil elastase activity compensates for a genetic lack of matrix metalloproteinase-9 (MMP-9) in leukocyte infiltration in a model of experimental peritonitis J. Leukoc. Biol., March 1, 2009; 85(3): 374 - 381. [Abstract] [Full Text] [PDF]

				J. W. Hollingsworth, S. R. Kleeberger, and W. M. Foster Ozone and Pulmonary Innate Immunity Proceedings of the ATS, July 1, 2007; 4(3): 240 - 246. [Abstract] [Full Text] [PDF]

				A. Linden, M. Laan, and G. P. Anderson Neutrophils, interleukin-17A and lung disease Eur. Respir. J., January 1, 2005; 25(1): 159 - 172. [Abstract] [Full Text] [PDF]

				J. G. Wagner, S. J. Van Dyken, J. R. Wierenga, J. A. Hotchkiss, and J. R. Harkema Ozone Exposure Enhances Endotoxin-Induced Mucous Cell Metaplasia in Rat Pulmonary Airways Toxicol. Sci., August 1, 2003; 74(2): 437 - 446. [Abstract] [Full Text] [PDF]

				M. Laan, L. Palmberg, K. Larsson, and A. Linden Free, soluble interleukin-17 protein during severe inflammation in human airways Eur. Respir. J., March 1, 2002; 19(3): 534 - 537. [Abstract] [Full Text] [PDF]