Abstract
Neutrophil elastase plays pivotal roles in the pathogenesis of pulmonary fibrosis. The neutrophil elastase inhibitor, sivelestat, could alleviate pulmonary fibrosis, however, the antifibrotic mechanisms have not yet been clarified. We examined the antifibrotic mechanisms, mainly focusing on a key fibrotic cytokine, transforming growth factor-β1, in this study.
To elucidate the antifibrotic mechanisms of sivelestat, we examined a murine model of bleomycin-induced early-stage pulmonary fibrosis. After intratracheal instillation of bleomycin, sivelestat was administered intraperitoneally once a day for 7 or 14 days. Bronchoalveolar lavage fluid and lung samples were examined on day 7 or day 14 after bleomycin instillation.
In the bleomycin-induced early-stage pulmonary fibrosis model, the neutrophil elastase level was increased in the lungs. Sivelestat significantly inhibited the increase of lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils, and lymphocytes), the levels of the active form of transforming growth factor-β1 and phospho-Smad2 in the bleomycin-induced early-stage pulmonary fibrosis. The total transforming growth factor-β1 levels and relative changes of transforming growth factor-β1 mRNA expression, however, were not decreased significantly by sivelestat.
These results suggested that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-β activation and inflammatory cell recruitment in the lung.
- ERS