Divergent roles for Clusterin in Lung Injury and Repair

Sci Rep. 2017 Nov 13;7(1):15444. doi: 10.1038/s41598-017-15670-5.


Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1. The fibrotic response in Clusterin deficient (CLU-/-) mice persisted after bleomycin and it was associated with increased DNA damage, reduced DNA repair responses, and elevated cellular senescence. Remarkably, this pattern mirrored that observed in IPF lung tissues. Together, our results show that cellular localization of Clusterin leads to divergent effects on epithelial cell regeneration and lung repair during fibrosis.

Publication types

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

MeSH terms

  • Aged
  • Animals
  • Apoptosis
  • Bleomycin / adverse effects
  • Case-Control Studies
  • Cell Line
  • Clusterin / blood
  • Clusterin / genetics
  • Clusterin / metabolism*
  • Cytoplasm / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Mismatch Repair
  • Datasets as Topic
  • Disease Models, Animal
  • Epithelial Cells / pathology
  • Extracellular Space / metabolism
  • Female
  • Fibrosis
  • Gene Expression Profiling
  • Gene Knockdown Techniques
  • Humans
  • Idiopathic Pulmonary Fibrosis / blood
  • Idiopathic Pulmonary Fibrosis / chemically induced
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / pathology*
  • Lung / drug effects
  • Lung / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Pulmonary Disease, Chronic Obstructive / blood
  • Pulmonary Disease, Chronic Obstructive / pathology*
  • RNA, Small Interfering / metabolism
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / pathology


  • CLU protein, human
  • Clu protein, mouse
  • Clusterin
  • RNA, Small Interfering
  • Bleomycin