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Keywords:

  • surfactant proteins;
  • Flk-1;
  • lung morphogenesis;
  • cell proliferation

Abstract

Members of the transforming growth factor β (TGF-β) family of polypeptides have been implicated in morphogenesis and differentiation in numerous tissues, including the lung. In order to further define effects of TGF-β signaling in lung morphogenesis, a constitutively active form of TGF-β1 was expressed in respiratory epithelial cells of the fetal mouse lung in vivo. Expression of TGF-β1 arrested lung morphogenesis in the pseudoglandular stage of development, inhibiting synthesis of differentiation-dependent proteins, SP-B, SP-C, and CCSP, and maintaining embryonic patterns of staining for thyroid transcription factor-1 (TTF-1) and hepatocyte nuclear factor-3β (HNF-3β). The pulmonary mesenchyme was thickened and vascular density was increased by TGF-β1. TGF-β1 decreased expression of vascular endothelial growth factor-A (VEGF-A) mRNA and protein, and the abundance of Flk-1 mRNA in the lung mesenchyme. Distribution of platelet-endothelial cell adhesion molecule (PECAM)-1, a marker of pulmonary blood vessels, was altered, and ultrastructural studies demonstrated that TGF-β1 inhibited vascular development in the fetal lung. TGF-β1 perturbed both epithelial cell differentiation and formation of the pulmonary vasculature, supporting the concept that precise control of signaling via the TGF-β receptor pathway is critical for normal lung morphogenesis. © 2001 Wiley-Liss, Inc.