Protective effects of endothelin-2 expressed in epithelial cells on bleomycin-induced pulmonary fibrosis in mice

Aristi Intan Soraya, Yoko Suzuki, Mitsuru Morimoto, Chemyong Jay Ko, Koji Ikeda, Ken Ichi Hirata, Noriaki Emoto

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)E61-E70
JournalKobe Journal of Medical Sciences
Issue number2
StatePublished - 2021


  • Endothelin-2
  • Epithelial cells
  • Fibroblast
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Medicine(all)


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