Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis.
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 beta1 integrins, are stimulated by transforming growth factor (TGF)-beta(1) in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-beta(1)-induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-beta(1) 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-beta(1) 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-beta(1)-induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-beta(1) and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-beta(1)-induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-beta(1), highlighting the importance of these findings for other fibrotic stimuli.
Kang
Hye-Ryun
HR
Section of Pulmonary and Critical Care Medicine and 2Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA.
Lee
Chun Geun
CG
Homer
Robert J
RJ
Elias
Jack A
JA
D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D003094:Collagen / Q000032:analysis; D004249:DNA Damage / Q000187:drug effects; D015151:Immunoblotting; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000473:pathology / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D039961:Semaphorins / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000633:toxicity*
D015703:Antigens, CD; D019012:Integrin beta1; D009419:Nerve Tissue Proteins; C492112:Plxna3 protein, mouse; D011956:Receptors, Cell Surface; C485571:Sema7a protein, mouse; D039961:Semaphorins; D053773:Transforming Growth Factor beta1; D003094:Collagen; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt