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J. Exp. Med. 204 (5): 1083-1093

Copyright © 2007 by the Rockefeller University Press.


ARTICLE

Semaphorin 7A plays a critical role in TGF-ß1–induced pulmonary fibrosis

Hye-Ryun Kang1, Chun Geun Lee1, Robert J. Homer2, , and Jack A. Elias1

1 Section of Pulmonary and Critical Care Medicine and 2 Department of Pathology, Yale University School of Medicine, New Haven, CT 06519

CORRESPONDENCE Jack A. Elias: jack.elias{at}yale.edu

Abstract: Semaphorin (SEMA) 7A regulates neuronal and immune function. In these studies, we tested the hypothesis that SEMA 7A is also a critical regulator of tissue remodeling. These studies demonstrate that SEMA 7A and its receptors, plexin C1 and ß1 integrins, are stimulated by transforming growth factor (TGF)-ß1 in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-ß1–induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-ß1 stimulated SEMA 7A via a largely Smad 3–independent mechanism and stimulated SEMA 7A receptors, matrix proteins, CCN proteins, fibroblast growth factor 2, interleukin 13 receptor components, proteases, antiprotease, and apoptosis regulators via Smad 2/3–independent and SEMA 7A–dependent mechanisms. SEMA 7A also played an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. TGF-ß1 and bleomycin also activated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB)/AKT via SEMA 7A–dependent mechanisms, and PKB/AKT inhibition diminished TGF-ß1–induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-ß1 and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-ß1–induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-ß1, highlighting the importance of these findings for other fibrotic stimuli.


Abbreviations used: BAL, bronchoalveolar lavage; Dox, doxycycline; ECM, extracellular matrix; Egr, early growth response protein; FGF, fibroblast growth factor; ICAD, inhibitor of caspase-activated DNase; IHC, immunohistochemistry; IPF, idiopathic pulmonary fibrosis; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; SEMA, semaphorin; Tg, transgene; TIMP, tissue inhibitor of metalloproteinase; TUNEL, TdT-mediated dUTP nick-end labeling.

H.-R. Kang and C.G. Lee contributed equally to this work.


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