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.     

The role of matrix metalloproteinases in the pathophysiology and progression of human nervous system malignancies: a chance for the development of targeted therapeutic approaches?

Background: Matrix metalloproteinases (MMPs) are a group of zinc- dependent endopeptidases involved in the degradation of extracellular matrix components. MMPs have been implicated in a wide variety of physiological processes, such as angiogenesis, wound healing and tissue remodeling. However, recent studies have revealed a significant role for MMPs in tumorigenesis pathophysiology and prediction of patients' clinical outcome. Alterations in the regulation of MMP expression are thought to play an important role in the development and progression of central nervous system (CNS) malignancies. Objective/methods: This study provides an up-to-date review of the literature on the pathophysiologic involvement of MMPs in the development and progression of human CNS malignancies, as well as the potential use of natural and/or synthetic MMP-inhibitors (MMPIs) as a targeted therapeutic approach to this group of neoplasms. Results/conclusions: The currently available data provide clear evidence for the involvement of MMPs in the pathophysiology of astrocytomas, glioblastomas, meningiomas, medulloblastomas/primitive neuroectodermal tumors and pituitary tumors. The use of MMPIs in the treatment of CNS malignancies has, until now, reached controversial (but mainly disappointing) results that can nevertheless provide the basis for further investigation. The co-administration of other agents, the use of surgery and/or radiation, and elimination of the MMPIs-induced adverse effects, as well as the use of antisense technology, might be the tools by which the natural and synthetic MMPIs could find their place in everyday clinical practice for the management of CNS malignancies.     

Proteolysis of extracellular matrix by invadopodiafacilitates human breast cancer cell invasion and ismediated by matrix metalloproteinases

Breast cancer cell lines vary in invasive behavior and one highly invasive cell line (MDA-MB-231)proteolytically degrades extracellular matrix with invadopodia (Thompson et al. 1992, J Cell Physiol, 150,534-44; Chen et al. 1994, Breast Cancer Res Treat, 31, 217-26). Invadopodial proteolysis of extracellularmatrix is thought to be necessary for invasion; however, this has not been demonstrated directly. To obtainsuch evidence, normal (HBL-100) and malignant (MCF-7, MDA-MB-231) breast cells were evaluated forinvadopodial proteolysis of extracellular matrix and invasive behavior. We report that invadopodial prote-olysisof immobilized fibronectin is positively correlated with invasion of cells into type I collagen gels.Moreover, reducing the proteolytic activity of invadopodia with the metalloproteinase inhibitor, batimastat(BB-94), also decreases invasion indicating that breast cancer cell invasion is dependent upon proteolyti-callyactive invadopodia. ©Kluwer Academic Publishers