The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice

Pharmacol Res. 2015 Sep;99:52-62. doi: 10.1016/j.phrs.2015.05.004. Epub 2015 May 22.

Abstract

The purpose of this study was to evaluate the role of CCAAT/enhancer-binding protein homologous protein (CHOP), an important transcription factor that regulates the inflammatory reaction during the endoplasmic reticulum (ER) stress response, in the development of pulmonary fibrosis induced by bleomycin (BLM) in mice. An intratracheal injection of BLM transiently increased the expression of CHOP mRNA and protein in an early phase (days 1 and 3) in mice lungs. BLM-induced pulmonary fibrosis was significantly attenuated in Chop gene deficient (Chop KO) mice, compared with wild-type (WT) mice. Furthermore, the inflammatory reactions evaluated by protein concentration, the total number of leucocytes and neutrophils in the bronchoalveolar lavage fluid (BALF), the mRNA expression of interleukin 1b and caspase 11, and the apoptotic cell death were suppressed in Chop KO mice compared with those in WT mice. In addition, administration of tauroursodeoxycholic acid (TUDCA), a pharmacological agent that can inhibit CHOP expression, inhibited the BLM-induced pulmonary fibrosis and inflammation, and the increase in Chop mRNA expression in WT mice in a dose-dependent manner. These results suggest that the ER stress-induced transcription factor, CHOP, at least in part, plays an important role in the development of BLM-induced pulmonary fibrosis in mice, and that the inhibition of CHOP expression by a pharmacological agent, such as TUDCA, may be a promising strategy for the prevention of pulmonary fibrosis.

Keywords: Bleomycin; CHOP; Ddit3; Endoplasmic reticulum stress; Pulmonary fibrosis; Tauroursodeoxycholic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Bleomycin / toxicity*
  • Disease Models, Animal
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / physiology
  • Gene Expression / drug effects
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / prevention & control*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Taurochenodeoxycholic Acid / pharmacology*
  • Transcription Factor CHOP / deficiency
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*

Substances

  • Ddit3 protein, mouse
  • RNA, Messenger
  • Bleomycin
  • Transcription Factor CHOP
  • Taurochenodeoxycholic Acid
  • ursodoxicoltaurine