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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

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.

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

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