Protective Effects of Endothelin-2 Expressed in Epithelial Cells on Bleomycin-Induced Pulmonary Fibrosis in Mice

Kobe J Med Sci. 2021 Nov 2;67(2):E61-E70.


Initially, endothelin (ET)-2 was described as an endothelium-derived vasoconstrictor. However, accumulating evidence suggests the involvement of ET-2 in non-cardiovascular physiology and disease pathophysiology. The deficiency of ET-2 in mice can be lethal, and such mice exhibit a distinct developmental abnormality in the lungs. Nonetheless, the definite role of ET-2 in the lungs remains unclear. The ET-2 isoform, ET-1, promotes pulmonary fibrosis in mice. Although endothelin receptor antagonists (ERAs) show improvements in bleomycin-induced pulmonary fibrosis in mouse models, clinical trials examining ERAs for pulmonary fibrosis treatment have been unsuccessful, even showing harmful effects in patients. We hypothesized that ET-2, which activates the same receptor as ET-1, plays a distinct role in pulmonary fibrosis. In this study, we showed that ET-2 is expressed in the lung epithelium, and ET-2 deletion in epithelial cells of mice results in the exacerbation of bleomycin-induced pulmonary fibrosis. ET-2 knockdown in lung epithelial cell lines resulted in increased apoptosis mediated via oxidative stress induction. In contrast to the effects of ET-1, which induced fibroblast activation, ET-2 hampered fibroblast activation in primary mouse lung fibroblast cells by inhibiting the TGF-β-SMAD2/3 pathway. Our results demonstrated the divergent roles of ET-1 and ET-2 in pulmonary fibrosis pathophysiology and suggested that ET-2, expressed in epithelial cells, exerts protective effects against the development of pulmonary fibrosis in mice.

Keywords: endothelin-2; epithelial cells; fibroblast; pulmonary fibrosis.

MeSH terms

  • Animals
  • Bleomycin / administration & dosage
  • Bleomycin / toxicity*
  • Endothelin-2 / metabolism*
  • Epithelial Cells
  • Epithelium / metabolism
  • Epithelium / pathology
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Pulmonary Fibrosis / chemically induced*
  • Pulmonary Fibrosis / metabolism*
  • Transforming Growth Factor beta / metabolism


  • Endothelin-2
  • Transforming Growth Factor beta
  • Bleomycin