Abstract
Carbon monoxide (CO) is a biologically active molecule produced in the body by the stress-inducible enzyme, heme oxygenase. We have previously shown that CO suppresses fibrosis in a murine bleomycin model. To investigate the mechanisms by which CO opposes fibrogenesis, we performed gene expression profiling of fibroblasts treated with transforming growth factor-beta(1) and CO. The most highly differentially expressed categories of genes included those related to muscular system development and the small proline-rich family of proteins. We confirmed in vitro, and in an in vivo bleomycin model of lung fibrosis, that CO suppresses alpha-smooth muscle actin expression and enhances small proline-rich protein-1a expression. We further show that these effects of CO depend upon signaling via the extracellular signal-regulated kinase pathway. Our results demonstrate novel transcriptional targets for CO and further elucidate the mechanism by which CO suppresses fibrosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actins / genetics
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Actins / metabolism*
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Administration, Inhalation
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Animals
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Bleomycin
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Bone Development / drug effects
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Carbon Monoxide / administration & dosage
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Carbon Monoxide / pharmacology*
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Cell Death / drug effects
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Cell Movement / drug effects
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Cells, Cultured
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Cornified Envelope Proline-Rich Proteins / genetics
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Cornified Envelope Proline-Rich Proteins / metabolism*
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblasts / drug effects*
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Fibroblasts / metabolism
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Gene Expression Profiling
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Lung / drug effects*
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Lung / metabolism
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MAP Kinase Signaling System / drug effects
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Male
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Mice
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Mice, Inbred C57BL
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Muscle Development / drug effects
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Organometallic Compounds / pharmacology*
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / genetics
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Pulmonary Fibrosis / metabolism
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Pulmonary Fibrosis / prevention & control*
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Time Factors
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Transforming Growth Factor beta1 / metabolism
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Ubiquitination / drug effects
Substances
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Actins
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Cornified Envelope Proline-Rich Proteins
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Organometallic Compounds
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Sprr1a protein, mouse
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Transforming Growth Factor beta1
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tricarbonylchloro(glycinato)ruthenium(II)
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Bleomycin
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Carbon Monoxide
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Extracellular Signal-Regulated MAP Kinases