Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis

J Exp Med. 2007 May 14;204(5):1083-93. doi: 10.1084/jem.20061273. Epub 2007 May 7.

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 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Antigens, CD / metabolism*
  • Apoptosis / drug effects
  • Collagen / analysis
  • DNA Damage / drug effects
  • Immunoblotting
  • Immunohistochemistry
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Integrin beta1 / metabolism
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Alveoli / pathology
  • Pulmonary Alveoli / physiology*
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / metabolism
  • Receptors, Cell Surface / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Semaphorins / metabolism*
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / toxicity*

Substances

  • Antigens, CD
  • Integrin beta1
  • Nerve Tissue Proteins
  • Plxna3 protein, mouse
  • Receptors, Cell Surface
  • Sema7a protein, mouse
  • Semaphorins
  • Transforming Growth Factor beta1
  • Collagen
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt