All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling

Ah Young Leem, Mi Hwa Shin, Ivor S. Douglas, Joo Han Song, Kyung Soo Chung, Eun Young Kim, Ji Ye Jung, Young Ae Kang, Joon Chang, Young Sam Kim, Moo Suk Park

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Abstract

The role of all-trans retinoic acid (ATRA) in pulmonary fibrosis is relatively unknown, although this metabolite modulates cell differentiation, proliferation, and development. We aimed to evaluate the role of ATRA in bleomycin-induced pulmonary fibrosis, and whether the mechanism involves EphA2-EphrinA1 and PI3K-Akt signaling. We evaluated three groups of mice: a control group (intraperitoneal DMSO injection 3 times weekly after PBS instillation), bleomycin group (intraperitoneal DMSO injection 3 times weekly after bleomycin instillation), and bleomycin + ATRA group (intraperitoneal ATRA injection 3 times weekly after bleomycin instillation). The cell counts and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology, Ashcroft score, hydroxyproline assay, expression of several signal pathway proteins including EphA2-EphrinA1, and PI3K-Akt, and cytokine levels were compared among the groups. We found that bleomycin significantly increased the protein concentration in the BALF, Ashcroft score in lung tissue, and hydroxyproline contents in lung lysates. Furthermore, bleomycin upregulated EphA2, EphrinA1, PI3K 110γ, Akt, IL-6 and TNF-α. However, administration of ATRA attenuated the upregulation of EphA2-EphrinA1 and PI3K-Akt after bleomycin instillation, and decreased pulmonary fibrosis. In addition, ATRA suppressed IL-6 and TNF-α production induced by bleomycin-induced injury. Collectively, these data suggest that ATRA attenuates bleomycin-induced pulmonary fibrosis by regulating EphA2-EphrinA1 and PI3K-Akt signaling.

Original languageEnglish
Pages (from-to)721-726
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume491
Issue number3
DOIs
Publication statusPublished - 2017 Sep 23

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All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Leem, A. Y., Shin, M. H., Douglas, I. S., Song, J. H., Chung, K. S., Kim, E. Y., Jung, J. Y., Kang, Y. A., Chang, J., Kim, Y. S., & Park, M. S. (2017). All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling. Biochemical and Biophysical Research Communications, 491(3), 721-726. https://doi.org/10.1016/j.bbrc.2017.07.122