Effects of neutrophil elastase inhibitor on bleomycin-induced pulmonary fibrosis in mice.

Neutrophils play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). To elucidate the possible involvement of neutrophil elastase (NE) in pulmonary fibrosis, we investigated the efficacy of a new specific NE inhibitor (ONO-5046 Na) in a murine model of human IPF, bleomycin-induced pulmonary fibrosis. Bronchoalveolar lavage (BAL) and histopathological analysis were performed on bleomycin-treated mice (group A), bleomycin and ONO-5046 Na-treated mice (group B), and saline control groups at 1, 15, and 29 d after the end of bleomycin treatment. At 29 d, multifocal fibrosis was observed in group A, whereas no fibrotic regions were observed in group B. Interleukin-1 beta and macrophage inflammatory protein-2 mRNA levels in BAL cells on day 1, and platelet-derived growth factor-A and insulin-like growth factor-1 mRNA levels on days 1 and 15, were significantly lower in group B than in group A. Thus, we demonstrated an inhibitory effect of ONO-5046. Na on pulmonary fibrosis in mice, indicating the involvement of NE in the pathogenesis of pulmonary fibrosis. We propose that this effect might be related to suppressed expression of particular cytokines in alveolar macrophages and that this specific NE inhibitor could be a novel therapeutic agent for IPF.