Abstract
Stimulation of cell signaling cascades by oxidants may be important in the pathogenesis of pulmonary and pleural diseases. Here, we demonstrate in rat pleural mesothelial cells that apoptotic concentrations of crocidolite asbestos and H2O2 induce phosphorylation and activation of extracellular signal-regulated protein kinases (ERK). Activation of c-jun-NH2-terminal protein kinases (JNK)/stress-activated protein kinases was also observed in response to H2O2. In contrast, asbestos caused more protracted activation of ERK without JNK activation. Both H2O2- and asbestos-induced activation of ERK was abolished by catalase. Moreover, chelation of surface iron from crocidolite fibers or addition of N-acetyl-L-cysteine prevented ERK activation and apoptosis by crocidolite, indicating an oxidative mechanism of cell signaling. The MEK1 inhibitor PD-98059 abrogated asbestos-induced apoptosis, confirming a causal relationship between ERK activation and apoptosis. These results suggest that distinct cell-signaling cascades may be important in phenotypic responses elicited by oxidant stresses.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylcysteine / pharmacology
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Asbestos / pharmacology*
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Asbestos, Crocidolite / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cells, Cultured
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / cytology
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Epithelial Cells / drug effects*
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Epithelial Cells / physiology
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Flavonoids / pharmacology
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Glutathione Transferase
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Hydrogen Peroxide / pharmacology*
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase Kinases*
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Mitogen-Activated Protein Kinases*
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Phosphorylation
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Pleura / cytology
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Pleura / drug effects*
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Pleura / physiology
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Rats
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Rats, Inbred F344
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / drug effects
Substances
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Enzyme Inhibitors
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Flavonoids
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Recombinant Fusion Proteins
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Asbestos, Crocidolite
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Asbestos
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Hydrogen Peroxide
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Glutathione Transferase
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Protein Kinases
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Acetylcysteine