Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis

Am J Pathol. 2005 Nov;167(5):1221-9. doi: 10.1016/S0002-9440(10)61210-2.

Abstract

The signal transducer and activator of transcription (Stat)-1 mediates growth arrest and apoptosis. We postulated that lung fibrosis characterized by excessive proliferation of lung fibroblasts would be enhanced in Stat1-deficient (Stat1-/-) mice. Two weeks after bleomycin aspiration (3 U/kg), Stat1-/- mice exhibited a more severe fibroproliferative response and significantly elevated total lung collagen compared to wild-type mice. Growth factors [epidermal growth factor (EGF) or platelet-derived growth factor (PDGF)] enhanced [3H]thymidine uptake in lung fibroblasts isolated from Stat1-/- mice compared to wild-type mice. Interferon (IFN)-gamma, which signals growth arrest via Stat1, inhibited EGF- or PDGF-stimulated mitogenesis in wild-type fibroblasts but enhanced [3H]thymidine uptake in Stat1-/- fibroblasts. Moreover, IFN-gamma treatment in the absence of growth factors induced a concentration-dependent increase in [3H]thymidine uptake in Stat1-/- but not wild-type fibroblasts. Mitogen-activated protein kinase (ERK-1/2) phosphorylation in response to PDGF or EGF did not differ among Stat1-/- and wild-type fibroblasts. However, Stat3 phosphorylation induced by PDGF, EGF, or IFN-gamma increased twofold in Stat1-/- fibroblasts compared to wild-type fibroblasts. Our findings indicate that Stat1-/- mice are more susceptible to bleomycin-induced lung fibrosis than wild-type mice due to 1) enhanced fibroblast proliferation in response to growth factors (EGF and PDGF), 2) stimulation of fibroblast growth by a Stat1-independent IFN-gamma signaling pathway, and 3) increased activation of Stat3.

Publication types

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

MeSH terms

  • Animals
  • Bleomycin / toxicity
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Collagen / analysis
  • Disease Models, Animal
  • Epidermal Growth Factor / pharmacology
  • Fibroblasts / pathology
  • Growth Inhibitors / pharmacology
  • Hydroxyproline / analysis
  • Interferon-gamma / pharmacology
  • Lung / drug effects
  • Lung / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Platelet-Derived Growth Factor / pharmacology
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / pathology*
  • Pulmonary Fibrosis / physiopathology
  • STAT1 Transcription Factor / genetics*
  • STAT1 Transcription Factor / physiology*
  • STAT3 Transcription Factor / metabolism
  • Thymidine / metabolism

Substances

  • Growth Inhibitors
  • Platelet-Derived Growth Factor
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Bleomycin
  • Epidermal Growth Factor
  • Interferon-gamma
  • Collagen
  • Mitogen-Activated Protein Kinase 3
  • Hydroxyproline
  • Thymidine