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

Publication ,  Journal Article
Walters, DM; Antao-Menezes, A; Ingram, JL; Rice, AB; Nyska, A; Tani, Y; Kleeberger, SR; Bonner, JC
Published in: Am J Pathol
November 2005

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.

Duke Scholars

Published In

Am J Pathol

DOI

ISSN

0002-9440

Publication Date

November 2005

Volume

167

Issue

5

Start / End Page

1221 / 1229

Location

United States

Related Subject Headings

  • Thymidine
  • STAT3 Transcription Factor
  • STAT1 Transcription Factor
  • Pulmonary Fibrosis
  • Platelet-Derived Growth Factor
  • Phosphorylation
  • Pathology
  • Mitogen-Activated Protein Kinase 3
  • Mice, Knockout
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
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Walters, D. M., Antao-Menezes, A., Ingram, J. L., Rice, A. B., Nyska, A., Tani, Y., … Bonner, J. C. (2005). Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis. Am J Pathol, 167(5), 1221–1229. https://doi.org/10.1016/S0002-9440(10)61210-2
Walters, Dianne M., Aurita Antao-Menezes, Jennifer L. Ingram, Annette B. Rice, Abraham Nyska, Yoshiro Tani, Steven R. Kleeberger, and James C. Bonner. “Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis.Am J Pathol 167, no. 5 (November 2005): 1221–29. https://doi.org/10.1016/S0002-9440(10)61210-2.
Walters DM, Antao-Menezes A, Ingram JL, Rice AB, Nyska A, Tani Y, et al. Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis. Am J Pathol. 2005 Nov;167(5):1221–9.
Walters, Dianne M., et al. “Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis.Am J Pathol, vol. 167, no. 5, Nov. 2005, pp. 1221–29. Pubmed, doi:10.1016/S0002-9440(10)61210-2.
Walters DM, Antao-Menezes A, Ingram JL, Rice AB, Nyska A, Tani Y, Kleeberger SR, Bonner JC. Susceptibility of signal transducer and activator of transcription-1-deficient mice to pulmonary fibrogenesis. Am J Pathol. 2005 Nov;167(5):1221–1229.
Journal cover image

Published In

Am J Pathol

DOI

ISSN

0002-9440

Publication Date

November 2005

Volume

167

Issue

5

Start / End Page

1221 / 1229

Location

United States

Related Subject Headings

  • Thymidine
  • STAT3 Transcription Factor
  • STAT1 Transcription Factor
  • Pulmonary Fibrosis
  • Platelet-Derived Growth Factor
  • Phosphorylation
  • Pathology
  • Mitogen-Activated Protein Kinase 3
  • Mice, Knockout
  • Mice