EXPRESSION AND ACTIVITY OF UROKINASE AND ITS RECEPTOR IN ENDOTHELIAL AND PULMONARY EPITHELIAL-CELLS EXPOSED TO ASBESTOS

An elongated endothelial cell phenotype, which demonstrated increased ICAM-1-dependent neutrophil adherence, was induced when these cells we re exposed to noncytotoxic concentrations of asbestos (Treadwell ct al ., Toxicol. Appl. Pharmacol. 139, 62-70, 1996). The present study exam ined mechanisms underlying this phenotypic change by investigating the effects of asbestos on transcription factor activation and expression of urokinase-type plasminogen activator (uPA) and its receptor uPAR. In situ zymography was used to compare the effects of these fibers on the activity of uPA. Cultures incubated with chrysotile or crocidolite asbestos, but not refractory ceramic fiber 1 (RCF-1), demonstrate loc alized cleavage of plasminogen, which was inhibited by amiloride. Immu nocytochemistry showed that chrysotile-stimulated uPA activity was ass ociated with a time-dependent augmentation of uPAR protein levels. RT- PCR analysis was used to investigate molecular mechanisms for these in creases. Chrysotile asbestos, but not RCF-1, increased endothelial cel l uPA message, relative to changes in beta-actin mRNA. This response t o asbestos was not limited to endothelial cells, since both uPA and uP AR mRNA levels increase in human bronchial epithelial BEAS-2B cells ex posed to chrysotile fibers. Finally, both types of asbestos, but not R CF-1, increased nuclear levels of nuclear factor-kappaB (NF-kappa B), a transcription factor common to increased expression of ICAM-1 and uP A. These data demonstrate that asbestos caused fiber-specific activati on of endothelial and pulmonary epithelial cells, resulting in phenoty pes capable of facilitating tissue remodeling. (C) 1998 Academic Press .