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J. Biol. Chem., Vol. 282, Issue 10, 7723-7732, March 9, 2007

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Transforming Growth Factor (TGF)-₁ Stimulates Pulmonary Fibrosis and Inflammation via a Bax-dependent, Bid-activated Pathway That Involves Matrix Metalloproteinase-12^*

Hye-Ryun Kang, Soo Jung Cho, Chun Geun Lee, Robert J. Homer, and Jack A. Elias¹

From the Section of Pulmonary and Critical Care Medicine and the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520

Fibrosis, apoptosis, and the exaggerated production of transforming growth factor (TGF)-₁ are juxtaposed in a variety of pulmonary diseases including the interstitial lung diseases and asthma. In these disorders, the relationships between these responses are not well defined. In addition, the apoptosis pathways that contribute to these responses and the mechanism(s) of their contribution have not been described. We hypothesized that BH3 domain-only protein-induced apoptosis plays an important role in the pathogenesis of TGF-₁-induced pulmonary responses. To test this hypothesis, we characterized the effects of transgenic TGF-₁ in mice with wild type (WT) and null Bax loci. To investigate the mechanisms of Bax activation and its effector functions, we also compared the effects of TGF-₁ in mice with WT and null Bid and matrix metalloproteinase (MMP)-12 loci, respectively. These studies demonstrate that TGF-₁ is a potent stimulator of Bax, Bid, and MMP-12. The studies also demonstrate that Bax and Bid play key roles in the pathogenesis of TGF-₁-induced inflammation, fibrosis, and apoptosis; that TGF-₁ stimulates MMP-12, TIMP-1, and cathepsins and inhibits MMP-9 and p21 via Bax- and Bid-dependent mechanisms; and that TGF-₁-stimulated pulmonary fibrosis is ameliorated in MMP-12-deficient animals. Finally, they demonstrate that Bax, Bid, and MMP-12 play similar roles in bleomycin-induced fibrosis, thereby highlighting the importance of this Bid-activated, Bax-mediated pathway and downstream MMP-12 in a variety of fibrogenic settings.

Received for publication, November 20, 2006 , and in revised form, January 4, 2007.

^* These studies were supported in part by National Institutes of Health Grants HL-56389 (to J. A. E.), HL-064242 (to J. A. E.), HL-078744 (to J. A. E.), and HL-084225 (to C. G. L.) and the postdoctoral fellowship program of the Korea Science & Engineering Foundation (KOSEF). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520-8057. Tel.: 203-737-4249; Fax: 203-785-3826; E-mail: jack.elias{at}yale.edu.

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