Carbon monoxide modulates alpha-smooth muscle actin and small proline rich-1a expression in fibrosis

Am J Respir Cell Mol Biol. 2009 Jul;41(1):85-92. doi: 10.1165/rcmb.2007-0401OC. Epub 2008 Dec 18.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / genetics
  • Actins / metabolism*
  • Administration, Inhalation
  • Animals
  • Bleomycin
  • Bone Development / drug effects
  • Carbon Monoxide / administration & dosage
  • Carbon Monoxide / pharmacology*
  • Cell Death / drug effects
  • Cell Movement / drug effects
  • Cells, Cultured
  • Cornified Envelope Proline-Rich Proteins / genetics
  • Cornified Envelope Proline-Rich Proteins / metabolism*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Gene Expression Profiling
  • Lung / drug effects*
  • Lung / metabolism
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Development / drug effects
  • Organometallic Compounds / pharmacology*
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / prevention & control*
  • Time Factors
  • Transforming Growth Factor beta1 / metabolism
  • Ubiquitination / drug effects

Substances

  • Actins
  • Cornified Envelope Proline-Rich Proteins
  • Organometallic Compounds
  • Sprr1a protein, mouse
  • Transforming Growth Factor beta1
  • tricarbonylchloro(glycinato)ruthenium(II)
  • Bleomycin
  • Carbon Monoxide
  • Extracellular Signal-Regulated MAP Kinases