Differential expression of matrix metalloproteinases and inhibitors in developing rat lung mesenchymal and epithelial cells.

Lung development requires extracellular matrix remodeling. This involves matrix metalloproteinases (MMPs) and their endogenous inhibitors [tissue inhibitors of metalloproteinases (TIMPs)]. Because these have been generally studied only in whole lung, we focused specifically on mesenchymal and epithelial cells freshly isolated at various developmental stages. In fibroblasts, the most striking developmental change was a peak (fourfold the prenatal level) of membrane type 1 (MT1)-MMP transcript during alveolarization, consistent with the known crucial role of MT1-MMP in this process. TIMP-1 and -2 mRNAs transiently increased on postnatal d (pn) 3. In alveolar epithelial cells (AECs), MMP-2 expression was maximal on fetal d (f) 19 when alveolar type II cells (ATII) differentiate and on pn5; by contrast, MT1-MMP expression changed little and TIMP-1 expression decreased with advancing gestation. In cells expressing in vitro the ATI phenotype, TIMP-1 and -2 activities were nine- and fivefold those in cells expressing ATII features, respectively, whereas ATII presented higher MMP-2 activity and were the only cell type to express MMP-9. This indicates higher remodeling potential for ATII. Pulmonary mesenchymal and epithelial cells have therefore quite distinct MMP/TIMP expression patterns. Changes in cell compartments should be specifically documented in developing lung diseases such as bronchopulmonary dysplasia in which changes in MMP activities have been reported.