TGFβ signaling in lung epithelium regulates bleomycin-induced alveolar injury and fibroblast recruitment

Am J Physiol Lung Cell Mol Physiol. 2011 Jun;300(6):L887-97. doi: 10.1152/ajplung.00397.2010. Epub 2011 Mar 25.

Abstract

The response of alveolar epithelial cells (AECs) to lung injury plays a central role in the pathogenesis of pulmonary fibrosis, but the mechanisms by which AECs regulate fibrotic processes are not well defined. We aimed to elucidate how transforming growth factor-β (TGFβ) signaling in lung epithelium impacts lung fibrosis in the intratracheal bleomycin model. Mice with selective deficiency of TGFβ receptor 2 (TGFβR2) in lung epithelium were generated and crossed to cell fate reporter mice that express β-galactosidase (β-gal) in cells of lung epithelial lineage. Mice were given intratracheal bleomycin (0.08 U), and the following parameters were assessed: AEC death by terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling assay, inflammation by total and differential cell counts from bronchoalveolar lavage, fibrosis by scoring of trichrome-stained lung sections, and total lung collagen content. Mice with lung epithelial deficiency of TGFβR2 had improved AEC survival, despite greater lung inflammation, after bleomycin administration. At 3 wk after bleomycin administration, mice with epithelial TGFβR2 deficiency showed a significantly attenuated fibrotic response in the lungs, as determined by semiquantitatve scoring and total collagen content. The reduction in lung fibrosis in these mice was associated with a marked decrease in the lung fibroblast population, both total lung fibroblasts and epithelial-to-mesenchymal transition-derived (S100A4(+)/β-gal(+)) fibroblasts. Attenuation of TGFβ signaling in lung epithelium provides protection from bleomycin-induced fibrosis, indicating a critical role for the epithelium in transducing the profibrotic effects of this cytokine.

Publication types

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

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Bleomycin / adverse effects*
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Disease Models, Animal
  • Epithelium / drug effects
  • Epithelium / metabolism*
  • Epithelium / pathology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fluorescent Antibody Technique
  • Lung Injury / chemically induced*
  • Lung Injury / metabolism
  • Lung Injury / pathology
  • Mice
  • Mice, Transgenic
  • Pneumonia / chemically induced
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Protein Serine-Threonine Kinases / physiology*
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / physiology*
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*
  • beta-Galactosidase / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Bleomycin
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • beta-Galactosidase