LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling

Hyunjung Kim, Sung Hyo Park, Song Yee Han, Yun Sil Lee, Jaeho Cho, Jin Mo Kim

Research output: Contribution to journalArticle

Abstract

Radiation therapy is an important modality in the treatment of lung cancer, but it can lead to radiation pneumonitis, and eventually radiation fibrosis. To date, only few available drugs can effectively manage radiation-induced pulmonary fibrosis. Lipoxins are endogenous molecules exhibit anti-inflammatory and pro-resolving effects. These molecules play a vital role in reducing excessive tissue injury and chronic inflammation; however, their effects on radiation-induced lung injury (RILI) are unknown. In this study, we investigated the effects of lipoxin A4 (LXA4) on RILI using our specialized small-animal model of RILI following focal-ablative lung irradiation (IR). LXA4 significantly inhibited immune-cell recruitment and reduced IR-induced expression of pro-inflammatory cytokines and fibrotic proteins in the lung lesion sites. In addition, micro-CT revealed that LXA4 reduced IR-induced increases in lung consolidation volume. The flexiVentTM assays showed that LXA4 significantly reversed IR-induced lung function damage. Moreover, LXA4 downregulated the activities of NF-κB and the Smad-binding element promoters. The expression of FPR2, an LXA4 receptor, increased during the development of IR-induced pulmonary fibrosis, whereas silencing of endogenous LXA4 using an antagonist (WRW4) or FPR2 siRNA resulted in impaired development of pulmonary fibrosis in response to IR. Collectively, these data suggest that LXA4 could serve as a potent therapeutic agent for alleviating RILI.

Original languageEnglish
Article number653
JournalCell Death and Disease
Volume11
Issue number8
DOIs
Publication statusPublished - 2020 Aug 1

Bibliographical note

Funding Information:
This work was supported by the Convergence of Conventional Medicine and Traditional Korean Medicine R&D program, funded by the Ministry of Health & Welfare through the Korea Health Industry Development Institute (HI15C0214), as well as by the Radiation Technology Research and Development Program (NRF-2017M2A2A7A02019612) and the Basic Science Research Program (NRF-2019R1A2C2086448) through the National Research Foundation of Korea (NRF) grant, funded by the Korea government (MSIT).

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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