The Journal of Experimental Medicine
Fluorescence In Vivo Endomicroscopy
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Published 2 August 2004. doi:10.1084/jem.20040104
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 3, 377-389
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Early Growth Response Gene 1–mediated Apoptosis Is Essential for Transforming Growth Factor ß1–induced Pulmonary Fibrosis

Chun Geun Lee1, Soo Jung Cho1, Min Jong Kang1, Svetlana P. Chapoval1, Patty J. Lee1, Paul W. Noble1, Teshome Yehualaeshet1, Binfeng Lu3, Richard A. Flavell3, Jeffrey Milbrandt4, Robert J. Homer2, and Jack A. Elias1

1 Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, 2 Department of Pathology and Pathology and Laboratory Medicine Service, VA-CT Health Care System, and 3 Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
4 Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110

Address correspondence to Jack A. Elias, Section of Pulmonary and Critical Care Medicine, Dept. of Internal Medicine, Yale University School of Medicine, 300 Cedar St., 441c TAC, New Haven, CT 06520. Phone: (203) 785-4163; Fax: (203) 785-3826; email: jack.elias{at}yale.edu

Fibrosis and apoptosis are juxtaposed in pulmonary disorders such as asthma and the interstitial diseases, and transforming growth factor (TGF)-ß1 has been implicated in the pathogenesis of these responses. However, the in vivo effector functions of TGF-ß1 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-ß1–induced responses have not been defined. To address these issues, we targeted bioactive TGF-ß1 to the murine lung using a novel externally regulatable, triple transgenic system. TGF-ß1 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-ß1–induced apoptosis. Interestingly, both interventions markedly ameliorated TGF-ß1–induced fibrosis and alveolar remodeling. These studies illustrate the complex effects of TGF-ß1 in vivo and define the critical role of Egr-1 in the TGF-ß1 phenotype. They also demonstrate that Egr-1–mediated apoptosis is a prerequisite for TGF-ß1–induced fibrosis and remodeling.

Key Words: asthma • pulmonary fibrosis • fibrosis reversibility • airway remodeling

Abbreviations used in this paper: BAL, bronchoalveolar lavage; Egr, early growth response gene; ICAD, inhibitor of caspase-activated DNase; IHC, immunohistochemistry; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; PARP, poly(ADP)ribose polymerase; rtTA, reverse tetracycline transactivator; tet-O, tetracycline operator; tTS, tetracycline-controlled transcriptional silencer; TUNEL, TdT-mediated dUTP nick-end labeling.


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