Asbestos exposure increases human bronchial epithelial cell fibrinolytic activity.
Chronic exposure to asbestos fibers results in fibrotic lung disease. The distal pulmonary epithelium is an early target of asbestos-mediated injury. Local plasmin activity may be important in modulating endoluminal inflammatory responses in the lung. We studied the effects of asbestos exposure on cell-mediated plasma clot lysis as a marker of pericellular plasminogen activation. Exposing human bronchial epithelial (HBE) cells to 100 micrograms/ml of asbestos fibers for 24 h resulted in increased plasma clot lysis. Fibrinolytic activity was augmented in a dose-dependent fashion, was not due to secreted protease, and occurred only when there was direct contact between the plasma clot and the epithelial monolayer. Further analysis showed that asbestos exposure increased HBE cell-associated urokinase-type plasminogen activator (uPA) activity in a time-dependent manner. The increased cell-associated PA activity could be removed by acid washing. The increase in PA activity following asbestos exposure required new protein synthesis because it was abrogated by treatment with either cycloheximide or actinomycin D. Therefore, asbestos exposure increases epithelial-mediated fibrinolysis by augmenting expression of uPA activity at the cell surface by mechanisms that require new RNA and protein synthesis. These observations suggest a novel mechanism whereby exposure of the distal epithelium to inhaled particulates may result in a chronic inflammatory response that culminates in the development of fibrotic lung disease.
Gross
T J
TJ
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242.
Cobb
S M
SM
Gruenert
D C
DC
Peterson
M W
MW
D001194:Asbestos / Q000009:adverse effects / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D005342:Fibrinolysis / Q000187:drug effects* / Q000502:physiology; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology
D005343:Fibrinolytic Agents; D001194:Asbestos; D003609:Dactinomycin; D003513:Cycloheximide; D014568:Urokinase-Type Plasminogen Activator