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Expression and activity of urokinase and its receptor in endothelial and pulmonary epithelial cells exposed to asbestos.

Authors
Barchowsky-A; Roussel-RR; Krieser-RJ; Mossman-BT; Treadwell-MD
Source
Toxicol Appl Pharmacol 1998 Oct; 152(2):388-396
NIOSHTIC No.
20030534
Abstract
An elongated endothelial cell phenotype, which demonstrated increased ICAM-1-dependent neutrophil adherence, was induced when these cells were exposed to noncytotoxic concentrations of asbestos (Treadwell et al., Toxicol. Appl. Pharmacol. 139, 62-70, 1996). The present study examined 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 localized cleavage of plasminogen, which was inhibited by amiloride. Immunocytochemistry showed that chrysotile-stimulated uPA activity was associated with a time-dependent augmentation of uPAR protein levels. RT-PCR analysis was used to investigate molecular mechanisms for these increases. Chrysotile asbestos, but not RCF-1, increased endothelial cell uPA message, relative to changes in beta-actin mRNA. This response to asbestos was not limited to endothelial cells, since both uPA and uPAR mRNA levels increase in human bronchial epithelial BEAS-2B cells exposed to chrysotile fibers. Finally, both types of asbestos, but not RCF-1, increased nuclear levels of nuclear factor-kappaB (NF-kappa B), a transcription factor common to increased expression of ICAM-1 and uPA. These data demonstrate that asbestos caused fiber-specific activation of endothelial and pulmonary epithelial cells, resulting in phenotypes capable of facilitating tissue remodeling.
Keywords
Asbestosis; Asbestos-fibers; Cell-cultures; Carcinogens; Lung; Pulmonary-system; In-vitro-studies
CODEN
TXAPA9
CAS No.
1332-21-4; 12001-29-5; 12001-28-4
Publication Date
19981001
Document Type
Journal Article
Email Address
barchowsky@dartmouth.edu
Funding Amount
76183
Funding Type
Grant
Fiscal Year
1999
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R03-OH-003267
Issue of Publication
2
ISSN
0041-008X
Source Name
Toxicology and Applied Pharmacology
State
NH; VT
Performing Organization
Dartmouth College, Hanover, New Hampshire
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