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

被引:286
作者
Lee, CG
Cho, SJ
Kang, MJ
Chapoval, SR
Lee, PJ
Noble, PW
Yehualaeshet, T
Lu, BF
Flavell, RA
Milbrandt, J
Homer, RJ
Elias, JA
机构
[1] Yale Univ, Sch Med, Dept Internal Med, Pulm & Crit Care Med Sect, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA
[3] Yale Univ, Sch Med, Lab Med Serv, VACT Hlth Care Syst, New Haven, CT 06520 USA
[4] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA
[5] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA
关键词
asthma; pulmonary fibrosis; fibrosis reversibility; airway remodeling;
D O I
10.1084/jem.20040104
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-pl-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.
引用
收藏
页码:377 / 389
页数:13
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