Early Growth Response Gene 1–mediated Apoptosis Is Essential for Transforming Growth Factor β1–induced Pulmonary Fibrosis

CG Lee, SJ Cho, MJ Kang, SP Chapoval… - The Journal of …, 2004 - rupress.org
CG Lee, SJ Cho, MJ Kang, SP Chapoval, PJ Lee, PW Noble, T Yehualaeshet, B Lu
The Journal of experimental medicine, 2004rupress.org
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 …
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.
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