Differential expression of the urokinase receptor in fibroblasts from normal and fibrotic human lungs.

Abstract

Binding of urokinase-type plasminogen activator (uPA) to a specific receptor (uPAR) on human lung fibroblasts enables it to regulate cellular proteolysis and remodeling of the extracellular matrix. Binding studies with radiolabeled uPA indicated that both normal and fibrotic lung fibroblasts express the receptor, but cells from fibrotic tissues bound significantly more uPA (P < 0.001). Phorbol myristate acetate, lipopolysaccharide, transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha) increased uPA binding and plasminogen activation at the cell surface, with a greater maximal effect on fibrotic than on normal fibroblasts. Excess unlabeled uPA, specific antibody, or antisense oligonucleotides inhibited uPA binding. Ribonuclease (RNase) protection assays showed higher levels of uPAR messenger ribonuleic acid (mRNA) in each of the five fibrotic cell lines than in normal fibroblasts. uPA was mitogenic for normal as well as fibrotic fibroblasts, indicating that receptor binding concurrently localizes cellular proteolytic activity and stimulates mitogenesis. Morphometry and immunohistochemical analysis showed that uPAR, as well as uPA, was increased in fibroblasts in fibrotic lung tissue. Increased expression of uPAR by fibrotic lung fibroblasts and enhanced urokinase binding induced by proinflammatory cytokines suggest a novel mechanism by which fibroblast-mediated matrix remodeling and proliferation may be regulated in interstitial lung diseases.

Induction of the Plasminogen Activator System Accompanies Peripheral Nerve Regeneration after Sciatic Nerve Crush

“…The increase of PA-dependent activity and PA mRNA at the crush site within 1 d of crush could be attributed to reactive and infiltrating neutrophils, macrophages, fibroblasts, and Schwann cells into the area of injury. All of these cell types express components of the PA system (Eaton et al, 1984;Heiple and Ossowski, 1986;Wilson and Francis, 1987;Grau and Moroz, 1989;Varani et al, 1992;Kung and Lau, 1993;Schafer et al, 1994;Rao et al, 1995;Kindzelskii et al, 1996;Shetty et al, 1996;Xiao et al, 1998). Additionally, we demonstrated with immunostaining that macrophages and neutrophils were present at the crush site within 1 d after crush injury (Fig.…”

Profiling of genes which are differentially expressed in mouse liver in response to adenoviral vectors and delivered genes

“…It has been shown that the expression of u-PAR is required for angiogenesis 23 and both TGF␤1 and CTGF genes are known to induce angiogenesis. 19,20 The observation that u-PAR is expressed in fibrotic fibroblasts and is responsible for cell migration and chemtotaxis, 24,25 which are also known functions of CTGF and TGF␤1, indicates that u-PAR may be induced by CTGF and TGF␤1 in wound repair.…”

Urokinase and its receptors in chronic kidney disease

“…In chronic renal tubulointerstitial disease the induction of endogenous uPAR reduces fibrosis severity while in a model of crescentic glomerulonephritis, genetic deficiency of either uPA or uPAR did not worsen glomerulosclerosis although the degree of glomerular inflammation was reduced in the uPAR−/− mice (22,50). In humans uPAR expression levels are higher on fibroblasts isolated form fibrotic lungs compared to normal lungs (123). In human keloid compared with normal scars, uPAR expression is enhanced (124).…”