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
相关论文
共 70 条
[31]   The involvement of Fas-Fas ligand pathway in fibrosing lung diseases [J].
Kuwano, K ;
Miyazaki, H ;
Hagimoto, N ;
Kawasaki, M ;
Fujita, M ;
Kunitake, R ;
Kaneko, Y ;
Hara, N .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1999, 20 (01) :53-60
[32]   Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor β1 [J].
Lee, CG ;
Homer, R ;
Zhou, Z ;
Lanone, Z ;
Wang, XM ;
Koteliansky, V ;
Shipley, JM ;
Gotwals, P ;
Noble, P ;
Chen, QS ;
Senior, RM ;
Elias, JA .
JOURNAL OF EXPERIMENTAL MEDICINE, 2001, 194 (06) :809-821
[33]  
Lee HS, 2001, HEPATO-GASTROENTEROL, V48, P1312
[34]   Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1) [J].
Lee, SL ;
Sadovsky, Y ;
Swirnoff, AH ;
Polish, JA ;
Goda, P ;
Gavrilina, G ;
Milbrandt, J .
SCIENCE, 1996, 273 (5279) :1219-1221
[35]   Regulation of immune responses by TGF-β [J].
Letterio, JJ ;
Roberts, AB .
ANNUAL REVIEW OF IMMUNOLOGY, 1998, 16 :137-161
[36]   Transforming growth factor-β1:: its anti-inflammatory and pro-fibrotic effects [J].
Ling, EM ;
Robinson, DS .
CLINICAL AND EXPERIMENTAL ALLERGY, 2002, 32 (02) :175-178
[37]   The transcription factor EGR-1 directly transactivates the fibronectin gene and enhances attachment of human glioblastoma cell line U251 [J].
Liu, CT ;
Yao, J ;
Mercola, D ;
Adamson, E .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (27) :20315-20323
[38]   Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema [J].
Majo, J ;
Ghezzo, H ;
Cosio, MG .
EUROPEAN RESPIRATORY JOURNAL, 2001, 17 (05) :946-953
[39]   Different cytokine profiles in cryptogenic fibrosing alveolitis and fibrosing alveolitis associated with systemic sclerosis - A quantitative study of open lung biopsies [J].
Majumdar, S ;
Li, D ;
Ansari, T ;
Pantelidis, P ;
Black, CM ;
Gizycki, M ;
du Bois, RM ;
Jeffery, PK .
EUROPEAN RESPIRATORY JOURNAL, 1999, 14 (02) :251-257
[40]   TGF-β1 and radiation fibrosis:: A master switch and a specific therapeutic target? [J].
Martin, M ;
Lefaix, JL ;
Delanian, S .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2000, 47 (02) :277-290