DIFFERENTIAL EXPRESSION OF THE UROKINASE RECEPTOR IN FIBROBLASTS FROMNORMAL AND FIBROTIC HUMAN LUNGS

Binding of urokinase-type plasminogen activator (uPA) to a specific re ceptor (uPAR) on human lung fibroblasts enables it to regulate cellula r proteolysis and remodeling of the extracellular matrix. Binding stud ies with radiolabeled uPA indicated that both normal and fibrotic lung fibroblasts express the receptor, but cells from fibrotic tissues bou nd significantly more uPA (P < 0.001). Phorbol myristate acetate, lipo -polysaccharide, transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) increased uPA binding and plasminog en activation at the cell surface, with a greater maximal effect on fi brotic than on normal fibroblasts. Excess unlabeled uPA, specific anti body, or antisense oligonucleotides inhibited uPA binding. Ribonucleas e (RNase) protection assays showed higher levels of uPAR messenger rib onuleic acid (mRNA) in each of the five fibrotic cell lines than in no rmal fibroblasts. uPA was mitogenic for normal as well as fibrotic fib roblasts, indicating that receptor binding concurrently localizes cell ular proteolytic activity and stimulates mitogenesis. Morphometry and immunohistochemical analysis showed that uPAR, as well as uPA, was inc reased in fibroblasts in fibrotic lung tissue. Increased expression of uPAR by fibrotic lung fibroblasts and enhanced urokinase binding indu ced by proinflammatory cytokines suggest a novel mechanism by which fi broblast-mediated matrix remodeling and proliferation may be regulated in interstitial lung diseases.