Nickel-induced plasminogen activator inhibitor-1 expression inhibits the fibrinolytic activity of human airway epithelial cells.
One cause of debilitating pulmonary fibrosis is inhalation of insoluble metals. Human epidemiological and animal studies have associated inhalation of nickel dusts with increased incidence of pulmonary fibrosis. However, specific mechanisms for nickel-induced pulmonary fibrosis have yet to be elucidated. The current studies examine the hypothesis that particulate nickel promotes pulmonary fibrosis by inhibiting the fibrinolytic cascade. Since the urokinase-type plasminogen activator (uPA) initiates this cascade, this hypothesis was tested by investigating the effects of noncytotoxic levels of nickel subsulfide on the balance of uPA expression relative to expression of its inhibitor, PAI-1, in cultured human bronchial epithelial cells (BEAS-2B). Exposure to the metal decreased secreted uPA protein levels and activity without affecting uPA mRNA levels. In contrast, these same exposures stimulated transcription of PAI-1, causing prolonged increases in both mRNA and protein levels. Despite partial recovery of uPA protein levels, uPA activity remained depressed for more than 48 h after exposure to nickel due to the continued increase in PAI-1 expression. These data indicate that particulate nickel inhibits the fibrinolytic cascade by increasing the ratio of plasminogen inhibitor to activator. Sustained loss of uPA activity may contribute to nickel-induced pulmonary fibrosis in exposed populations.
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Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Barchowsky
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D001980:Bronchi / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D009532:Nickel / Q000633:toxicity*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000139:chemically induced; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000235:genetics
D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D009532:Nickel; D014568:Urokinase-Type Plasminogen Activator; C017557:nickel subsulfide