Involvement of serum response factor isoforms in myofibroblast differentiation during bleomycin-induced lung injury

Am J Respir Cell Mol Biol. 2003 Nov;29(5):583-90. doi: 10.1165/rcmb.2002-0315OC. Epub 2003 May 30.

Abstract

Serum response factor (SRF) is a transcription factor essential for smooth muscle (SM) myogenesis. Its role in myofibroblast differentiation is, however, unknown. We studied the expression and the localization of SRF in bleomycin-induced pulmonary fibrosis, where myofibroblasts are abundant. We found that SRF levels were upregulated in bleomycin-exposed mouse lungs mainly due to de novo synthesis of SRFDelta5, a less myogenic SRF isoform. Before myofibroblast differentiation, SRF/SRFDelta5 was immunolocalized mostly in the cytoplasm of scattered fibroblasts at lesion sites. With the development of myofibroblasts, however, SRF/SRFDelta5 was found in myofibroblast nuclei. cDNA array analysis showed that SRFDelta5 and SRF induced expression of transforming growth factor-beta1, a critical factor in myofibroblast differentiation. This was accompanied by de novo expression of several inflammatory cell-specific mRNAs. The latter was confirmed by reverse transcriptase-polymerase chain reaction. Treatment of lung fibroblasts with tumor necrosis factor-alpha, which is produced early in the bleomycin model, induced SRFDelta5 expression and SRF/SRFDelta5 cytoplasmic accumulation, whereas addition of transforming growth factor-beta1 caused SRF/SRFDelta5 nuclear translocation followed by SM alpha-actin synthesis. Interleukin-4, another cytokine involved in myofibroblast differentiation, did not affect SRF or induce SRFDelta5 expression. Our studies therefore suggested a new mechanism whereby SRF and SRFDelta5 contribute to the emergence of myofibroblasts in lung injury and fibrosis.

Publication types

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

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / pharmacology*
  • Bleomycin / adverse effects
  • Bleomycin / pharmacology*
  • Cell Differentiation / physiology
  • Female
  • Fibroblasts / physiology*
  • Lung / drug effects*
  • Mice
  • Protein Isoforms
  • Serum Response Factor / genetics*
  • Serum Response Factor / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Protein Isoforms
  • Serum Response Factor
  • Bleomycin