Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor batimastat.
Bleomycin-induced pulmonary fibrosis is known to be associated with the increased activity of two gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, in bronchoalveolar lavage (BAL). This study has investigated the effect of a synthetic inhibitor of MMP, batimastat, on the development of pulmonary fibrosis induced by bleomycin administration in mice. Animals were intranasally instilled with saline or bleomycin (0.5 mg in 100 microl per mouse). Batimastat (30 mg/kg) or vehicle alone was administered by intraperitoneal injection 24 h and 1 h before saline or bleomycin instillation, and then daily at the same dosage until the end of the study. Fifteen days after bleomycin administration, BAL was performed and the lung was removed. Treatment of mice with batimastat significantly reduced bleomycin-induced lung fibrosis, as shown in the lung by histopathological examination and by a decrease in hydroxyproline levels. Batimastat also prevented the increase in BAL macrophage and lymphocyte numbers, whereas it did not show any effect on the increased expression of active transforming growth factor-beta (TGF-beta) in BAL. Batimastat treatment was effective in reducing MMP-2 and MMP-9 activity as well as the tissue inhibitor of metalloproteinase-1 (TIMP-1) level in BAL. These results suggest that administration of the MMP inhibitor batimastat is useful in preventing experimental pulmonary fibrosis induced by bleomycin and raises the possibility of a therapeutic approach to human pulmonary fibrotic disease.
INSERM U 456, Laboratoire de Pharmacodynamie et de Pharmacologie Moléculaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, Avenue du Prof. Léon Bernard, 35043 Rennes Cedex, France.
M
M
Corbel
S
S
Caulet-Maugendre
N
N
Germain
S
S
Molet
V
V
Lagente
E
E
Boichot
D000818:Animals; D001761:Bleomycin; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D013876:Thiophenes / Q000627:therapeutic use*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013876:Thiophenes; D019714:Tissue Inhibitor of Metalloproteinases; D001761:Bleomycin; D010649:Phenylalanine; C080985:batimastat; D008666:Metalloendopeptidases; D006909:Hydroxyproline