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

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.