Semaphorin 7A plays a critical role in TGF-β1-induced pulmonary fibrosis

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 β1 integrins, are stimulated by transforming growth factor (TGF)-β1 in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-β1-induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-β1 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-β1 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- β1-induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-β1 and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-β1-induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF- β1, highlighting the importance of these findings for other fibrotic stimuli. JEM © The Rockefeller University Press.