Insufficient autophagy in idiopathic pulmonary fibrosis

Am J Physiol Lung Cell Mol Physiol. 2013 Jan 1;304(1):L56-69. doi: 10.1152/ajplung.00213.2012. Epub 2012 Oct 19.


Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation, and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type-specific manner and is a promising clue for understanding the pathogenesis of IPF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Autophagy*
  • Cell Differentiation / physiology
  • Cellular Senescence / physiology
  • Endoplasmic Reticulum Stress / physiology
  • Epithelial Cells / pathology
  • Epithelial Cells / physiology
  • Humans
  • Idiopathic Pulmonary Fibrosis / physiopathology*
  • Myofibroblasts / cytology
  • Sequestosome-1 Protein
  • Tunicamycin / pharmacology
  • Ubiquitin / biosynthesis


  • Adaptor Proteins, Signal Transducing
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Ubiquitin
  • Tunicamycin