Absence of Thy-1 results in TGF-Β induced MMP-9 expression and confers a profibrotic phenotype to human lung fibroblasts

Academic Article

Abstract

  • Fibroblasts differ in a variety of phenotypic features, including the expression of Thy-1 a glycophosphatidylinositol-linked glycoprotein. Fibroblasts in idiopathic pulmonary fibrosis (IPF) are Thy-1 negative, whereas most fibroblasts from normal lungs are Thy-1 positive. However, the functional consequences of the absence of Thy-1 are not fully understood. We analyzed the expression of Thy-1 in several primary fibroblasts lines derived from IPF, hypersensitivity pneumonitis (HP), and normal human lungs. We found that a high proportion, independently of their origin, expressed Thy-1 in vitro. We identified a primary culture of HP fibroblasts, which did not express Thy-1, and compared several functional activities between Thy-1 (-) and Thy-1 (-) fibroblasts. Thy-1 (-) fibroblasts were smaller (length: 41.320.8 versus 83.140 ), showed increased proliferative capacity and enhanced PDGF-induced transmigration through collagen I (59.9% versus 42.2% over control under basal conditions, P0.01). Likewise, Thy-1 (-) fibroblasts either spontaneously or after TGF-Β stimulation demonstrated stronger contraction of collagen matrices (eg, 0.170.03 versus 0.60.05 cm 2 after TGF-Β stimulation at 24 h; P0.01). Thy-1 (-) lung fibroblasts stimulated with TGF-Β1 expressed MMP-9, an enzyme that is usually not produced by lung fibroblasts. TGFΒ-induced MMP-9 expression was reversible upon re-expression of Thy-1 after transfection with full-length Thy-1. Β-glycan, a TGF-Β receptor antagonist abolished MMP-9 expression. TGF-Β1-induced MMP-9 in Thy-1 (-) fibroblasts depended on the activation of ERK1/2 signaling pathway. Finally, we demonstrated that fibroblasts from IPF fibroblastic foci, which do not express Thy-1 exhibit strong staining for immunoreactive MMP-9 protein in vivo. These findings indicate that loss of Thy-1 in human lung fibroblasts induces a fibrogenic phenotype. © 2011 USCAP, Inc All rights reserved.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Ramírez G; Hagood JS; Sanders Y; Ramírez R; Becerril C; Segura L; Barrera L; Selman M; Pardo A
  • Start Page

  • 1206
  • End Page

  • 1218
  • Volume

  • 91
  • Issue

  • 8