title: A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice.
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 (TGF)-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 in lung collagen content, fibrotic changes, the numbers of total cells (including macrophages, neutrophils and lymphocytes), the levels of the active form of TGF-β1 and phospho-Smad2 in bleomycin-induced early-stage pulmonary fibrosis. The total TGF-β1 levels and relative changes of TGF-β1 mRNA expression, however, were not decreased significantly by sivelestat. These results suggest that sivelestat alleviated bleomycin-induced pulmonary fibrosis via inhibition of both TGF-β activation and inflammatory cell recruitment in the lung.
authors.affiliation: Dokkyo Medical University School of Medicine, Tochigi,  Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takemasa
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D018893:Bronchoalveolar Lavage; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007249:Inflammation; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D051899:Smad2 Protein / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D015842:Serine Proteinase Inhibitors; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D003094:Collagen; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine