Cathepsin E promotes pulmonary emphysema via mitochondrial fission

Am J Pathol. 2014 Oct;184(10):2730-41. doi: 10.1016/j.ajpath.2014.06.017.

Abstract

Emphysema is characterized by loss of lung elasticity and irreversible air space enlargement, usually in the later decades of life. The molecular mechanisms of emphysema remain poorly defined. We identified a role for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing. We examined lung tissue sections of persons with chronic obstructive pulmonary disease, a clinical entity that includes emphysematous change. Human chronic obstructive pulmonary disease lungs had markedly increased cathepsin E protein in the lung epithelium. We generated lung epithelial-targeted transgenic cathepsin E mice and found that they develop emphysema. Overexpression of cathepsin E resulted in increased E3 ubiquitin ligase parkin, mitochondrial fission protein dynamin-related protein 1, caspase activation/apoptosis, and ultimately loss of lung parenchyma resembling emphysema. Inhibiting dynamin-related protein 1, using a small molecule inhibitor in vitro or in vivo, inhibited cathepsin E-induced apoptosis and emphysema. To the best of our knowledge, our study is the first to identify links between cathepsin E, mitochondrial fission, and caspase activation/apoptosis in the pathogenesis of pulmonary emphysema. Our data expand the current understanding of molecular mechanisms of emphysema development and may provide new therapeutic targets.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Bronchoalveolar Lavage
  • Cathepsin E / genetics
  • Cathepsin E / metabolism*
  • Humans
  • Lung / metabolism
  • Lung / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Dynamics*
  • Oligopeptides / pharmacology
  • Pulmonary Emphysema / metabolism*
  • Pulmonary Emphysema / physiopathology
  • Quinazolinones / pharmacology
  • Smoke / adverse effects
  • Tobacco Smoke Pollution / adverse effects

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Oligopeptides
  • Quinazolinones
  • Smoke
  • Tobacco Smoke Pollution
  • benzyloxycarbonyl-valyl-alanyl-aspartic acid
  • Cathepsin E
  • Ctse protein, mouse
  • CTSE protein, human