Autophagy in idiopathic pulmonary fibrosis

PLoS One. 2012;7(7):e41394. doi: 10.1371/journal.pone.0041394. Epub 2012 Jul 18.

Abstract

Background: Autophagy is a basic cellular homeostatic process important to cell fate decisions under conditions of stress. Dysregulation of autophagy impacts numerous human diseases including cancer and chronic obstructive lung disease. This study investigates the role of autophagy in idiopathic pulmonary fibrosis.

Methods: Human lung tissues from patients with IPF were analyzed for autophagy markers and modulating proteins using western blotting, confocal microscopy and transmission electron microscopy. To study the effects of TGF-β(1) on autophagy, human lung fibroblasts were monitored by fluorescence microscopy and western blotting. In vivo experiments were done using the bleomycin-induced fibrosis mouse model.

Results: Lung tissues from IPF patients demonstrate evidence of decreased autophagic activity as assessed by LC3, p62 protein expression and immunofluorescence, and numbers of autophagosomes. TGF-β(1) inhibits autophagy in fibroblasts in vitro at least in part via activation of mTORC1; expression of TIGAR is also increased in response to TGF-β(1). In the bleomycin model of pulmonary fibrosis, rapamycin treatment is antifibrotic, and rapamycin also decreases expression of á-smooth muscle actin and fibronectin by fibroblasts in vitro. Inhibition of key regulators of autophagy, LC3 and beclin-1, leads to the opposite effect on fibroblast expression of á-smooth muscle actin and fibronectin.

Conclusion: Autophagy is not induced in pulmonary fibrosis despite activation of pathways known to promote autophagy. Impairment of autophagy by TGF-β(1) may represent a mechanism for the promotion of fibrogenesis in IPF.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Animals
  • Apoptosis Regulatory Proteins / biosynthesis
  • Autophagy*
  • Beclin-1
  • Cell Lineage
  • Fibroblasts / metabolism
  • Fibronectins / biosynthesis
  • Gene Expression Regulation
  • Homeostasis
  • Humans
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Intracellular Signaling Peptides and Proteins / biosynthesis
  • Lung / metabolism
  • Lung / pathology
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence / methods
  • Microtubule-Associated Proteins / biosynthesis
  • Multiprotein Complexes / biosynthesis
  • Phosphoric Monoester Hydrolases
  • Sequestosome-1 Protein
  • TOR Serine-Threonine Kinases / biosynthesis
  • Transforming Growth Factor beta / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Fibronectins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Transforming Growth Factor beta
  • light chain 3, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Phosphoric Monoester Hydrolases
  • TIGAR protein, human