Asbestos upregulates expression of the urokinase-type plasminogen activator receptor on mesothelial cells

Inhalation of asbestos is associated with pathologic changes in the pleural space, including pleural thickening, pleural plaques, and mesothelioma. Th ese processes are characterized by altered local proteolysis, cellular prol iferation, and cell migration, suggesting that the urokinase-type plasminog en activator receptor (uPAR) could be involved in the pathogenesis of asbes tos-induced pleural disease. We hypothesized that mesothelial cell uPAR exp ression is induced by exposure to asbestos. To test this hypothesis, we use d complementary techniques in rabbit and human mesothelial cells to determi ne whether uPAR expression is altered by exposure to asbestos. uPAR express ion was induced by chrysotile and crocidolite asbestos, but not by wollasto nite, as indicated by binding of radiolabeled urokinase-type plasminogen ac tivator (uPA) to rabbit or human mesothelial cells, uPA was not induced by fiber exposure. Exposure to exogenous uPA increased uPA activity of cells e xposed to wollastonite but not asbestos-treated MeT5A cells. uPAR expressio n increased further when asbestos was preincubated with vitronectin (VN) or serum. Increases in uPAR expression were confirmed by binding of uPA to uP AR in cell membrane preparations and immunofluorescent staining of uPAR at the cell surface, and were associated with increases in steady-state uPAR m essenger RNA. Mesothelial cell uPAR expression was also induced by media fr om monocytes cultured with asbestos incubated with VN and serum. By antibod y neutralization, the latter effect appeared to be in part mediated by tran sforming growth factor-beta. We found that asbestos increases uPAR at the s urface of rabbit and human mesothelial cells, suggesting that altered expre ssion of this receptor could be involved in asbestos-induced remodeling of the pleural mesothelium.