Involvement of mast cell chymase in bleomycin-induced pulmonary fibrosis in mice.
The possible role of mast cell chymase in organ fibrosis was examined using a bleomycin-induced pulmonary fibrosis model in mice. Intratracheal injection of bleomycin to mice significantly increased not only hydroxyproline content but also chymase activity in the lung. Administration of a chymase inhibitor SUN C8077 (7-chloro-3-(3-amynophenyl) quinazoline-2, 4-dione methanesulfonate) dose-dependently reversed the bleomycin-induced increase in hydroxyproline content as well as chymase activity in the lung. Human chymase digested latent transforming growth factor-beta1 (TGF-beta1) to form mature TGF-beta1 in vitro, which was inhibited by SUN C8077. Human chymase, on the other hand, failed to stimulate DNA synthesis of human lung fibroblasts CCD-8Lu and LL97A. Taken together, it is suggested that mast cell chymase might participate in the pathogenesis of pulmonary fibrosis, and that the chymase-induced fibrosis might be mediated at least in part by TGF-beta1. Chymase inhibitor may be promising for treatment of pulmonary fibrosis in humans.
Daiichi Suntory Biomedical Research Limited, 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8513, Japan.
Yoshiaki
Y
Tomimori
Tsuyoshi
T
Muto
Kayo
K
Saito
Taisaku
T
Tanaka
Hiroshi
H
Maruoka
Motoo
M
Sumida
Harukazu
H
Fukami
Yoshiaki
Y
Fukuda
D000818:Animals; D000903:Antibiotics, Antineoplastic; D001711:Biotransformation; D001761:Bleomycin; D053818:Chymases; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D008813:Mice, Inbred ICR; D008934:Mitogens / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D011994:Recombinant Proteins; D012697:Serine Endopeptidases / Q000494:pharmacology / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D008934:Mitogens; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D012697:Serine Endopeptidases; D053818:Chymases; D006909:Hydroxyproline