Early growth response gene 1-mediated apoptosis is essential for transforming growth factor β1-induced pulmonary fibrosis

Chun Geun Lee, Soo Jung Cho, Min Jong Kang, Svetlana P. Chapoval, Patty J. Lee, Paul W. Noble, Teshome Yehualaeshet, Binfeng Lu, Richard A. Flavell, Jeffrey Milbrandt, Robert J. Homer, Jack A. Elias

Research output: Contribution to journalArticle

281 Scopus citations

Abstract

Fibrosis and apoptosis are juxtaposed in pulmonary disorders such as asthma and the interstitial diseases, and transforming growth factor (TGF)-β1 has been implicated in the pathogenesis of these responses. However, the in vivo effector functions of TGF-β1 in the lung and its roles in the pathogenesis of these responses are not completely understood. In addition, the relationships between apoptosis and other TGF-β1-induced responses have not been defined. To address these issues, we targeted bioactive TGF-β1 to the murine lung using a novel externally regulatable, triple transgenic system. TGF-β1 produced a transient wave of epithelial apoptosis that was followed by mononuclear-rich inflammation, tissue fibrosis, myofibroblast and myocyte hyperplasia, and septal rupture with honeycombing. Studies of these mice highlighted the reversibility of this fibrotic response. They also demonstrated that a null mutation of early growth response gene (Egr)-1 or caspase inhibition blocked TGF-β1-induced apoptosis. Interestingly, both interventions markedly ameliorated TGF-β1-induced fibrosis and alveolar remodeling. These studies illustrate the complex effects of TGF-β1 in vivo and define the critical role of Egr-1 in the TGF-β1 phenotype. They also demonstrate that Egr-1-mediated apoptosis is a prerequisite for TGF-β1-induced fibrosis and remodeling.

Original languageEnglish
Pages (from-to)377-389
Number of pages13
JournalJournal of Experimental Medicine
Volume200
Issue number3
DOIs
StatePublished - Aug 2 2004

Keywords

  • Airway remodeling
  • Asthma
  • Fibrosis reversibility
  • Pulmonary fibrosis

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    Lee, C. G., Cho, S. J., Kang, M. J., Chapoval, S. P., Lee, P. J., Noble, P. W., Yehualaeshet, T., Lu, B., Flavell, R. A., Milbrandt, J., Homer, R. J., & Elias, J. A. (2004). Early growth response gene 1-mediated apoptosis is essential for transforming growth factor β1-induced pulmonary fibrosis. Journal of Experimental Medicine, 200(3), 377-389. https://doi.org/10.1084/jem.20040104