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 inc reased activity of two gelatinases, matrix metalloproteinase (MMP)-2 and MM P-9, in bronchoalveolar lavage (BAI,), This study has investigated the effe ct of a synthetic inhibitor of MMP, batimastat, on the development of pulmo nary fibrosis induced by bleomycin administration in mice. Animals were int ranasally instilled with saline or bleomycin (0.5 mg in 100 mul 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 d aily at the same dosage until the end of the study. Fifteen days after bleo mycin administration, BAL was performed and the lung was removed. Treatment of mice with batimastat significantly reduced bleomycin-induced lung fibro sis, as shown in the lung by histopathological examination and by a decreas e in hydroxyproline levels. Batimastat also prevented the increase in BAL m acrophage 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 acti vity as well as the tissue inhibitor of metalloproteinase-1 (TIMP-1) level in BAL, These results suggest that administration of the MMP inhibitor bati mastat is useful in preventing experimental pulmonary fibrosis induced by b leomycin and raises the possibility of a therapeutic approach to human pulm onary fibrotic disease. Copyright (C) 2001 John Wiley & Sons, Ltd.