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redox signaling, to induce plasminogen activator inhibitor-1
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755
Human epidemiological
and animal studies have associated inhalation of nickel dusts with an
increased incidence of pulmonary fibrosis. At the cellular level,
particulate nickel subsulfide inhibits fibrinolysis by
transcriptionally inducing expression of plasminogen activator
inhibitor (PAI)-1, an inhibitor of the urokinase-type plasminogen
activator. Because nickel is known to mimic hypoxia, the present study
examined whether nickel transcriptionally activates PAI-1 through the
hypoxia-inducible factor (HIF)-1
signaling pathway. The involvement
of the NADPH oxidase complex, reactive oxygen species, and kinases in
mediating nickel-induced HIF-1 signaling was also investigated.
Addition of nickel to BEAS-2B human airway epithelial cells increased
HIF-1 protein levels and elevated PAI-1 mRNA levels. Pretreatment of
cells with the extracellular signal-regulated kinase inhibitor U-0126
partially blocked HIF-1 protein and PAI-1 mRNA levels induced by
nickel, whereas antioxidants and NADPH oxidase inhibitors had no
effect. Pretreating cells with antisense, but not sense,
oligonucleotides to HIF-1 mRNA abolished nickel-stimulated increases
in PAI-1 mRNA. These data indicate that signaling through extracellular signal-regulated kinase and HIF-1 is required for nickel-induced transcriptional activation of PAI-1.
reduced nicotinamide adenine dinucleotide phosphate oxidase; nickel subsulfide; pulmonary fibrosis; mitogen-activated protein kinase; airway epithelium
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