Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis.

Published

Journal Article

Fibrosis and apoptosis are juxtaposed in pulmonary disorders such as asthma and the interstitial diseases, and transforming growth factor (TGF)-beta(1) has been implicated in the pathogenesis of these responses. However, the in vivo effector functions of TGF-beta(1) 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-beta(1)-induced responses have not been defined. To address these issues, we targeted bioactive TGF-beta(1) to the murine lung using a novel externally regulatable, triple transgenic system. TGF-beta(1) 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-beta(1)-induced apoptosis. Interestingly, both interventions markedly ameliorated TGF-beta(1)-induced fibrosis and alveolar remodeling. These studies illustrate the complex effects of TGF-beta(1) in vivo and define the critical role of Egr-1 in the TGF-beta(1) phenotype. They also demonstrate that Egr-1-mediated apoptosis is a prerequisite for TGF-beta(1)-induced fibrosis and remodeling.

Full Text

Cited Authors

  • Lee, CG; Cho, SJ; Kang, MJ; Chapoval, SP; Lee, PJ; Noble, PW; Yehualaeshet, T; Lu, B; Flavell, RA; Milbrandt, J; Homer, RJ; Elias, JA

Published Date

  • August 2004

Published In

Volume / Issue

  • 200 / 3

Start / End Page

  • 377 - 389

PubMed ID

  • 15289506

Pubmed Central ID

  • 15289506

Electronic International Standard Serial Number (EISSN)

  • 1540-9538

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.20040104

Language

  • eng