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RILI can be divided into radiation pneumonia (RP) and radiation\u2010induced lung fibrosis (RILF). Once RILF occurs, patients will eventually develop irreversible respiratory failure; thus, a new treatment strategy to prevent RILI is urgently needed. This study explored the therapeutic effect of pirfenidone (PFD), a Food and Drug Administration (FDA)\u2010approved drug for (IPF) treatment, and its mechanism in the treatment of RILF. In vivo, C57BL\/6 mice received a 50\u00a0Gy dose of X\u2010ray radiation to the whole thorax with or without the administration of PFD. Collagen deposition and fibrosis in the lung were reversed by PFD treatment, which was associated with reduced M2 macrophage infiltration and inhibition of the transforming growth factor\u2010\u03b21 (TGF\u2010\u03b21)\/Drosophila mothers against the decapentaplegic 3 (Smad3) signalling pathway. Moreover, PFD treatment decreased the radiation\u2010induced expression of TGF\u2010\u03b21 and phosphorylation of Smad3 in alveolar epithelial cells (AECs) and vascular endothelial cells (VECs). Furthermore, IL\u20104\u2013induced M2 macrophage polarization and IL\u201013\u2013induced M2 macrophage polarization were suppressed by PFD treatment in vitro, resulting in reductions in the release of arginase\u20101 (ARG\u20101), chitinase 3\u2010like 3 (YM\u20101) and TGF\u2010\u03b21. Notably, the PFD\u2010induced inhibitory effects on M2 macrophage polarization were associated with downregulation of nuclear factor kappa\u2010B (NF\u2010\u03baB) p50 activity. Additionally, PFD could significantly inhibit ionizing radiation\u2010induced chemokine secretion in MLE\u201012 cells and consequently impair the migration of RAW264.7 cells. PFD could also eliminate TGF\u2010\u03b21 from M2 macrophages by attenuating the activation of TGF\u2010\u03b21\/Smad3. In conclusion, PFD is a potential therapeutic agent to ameliorate fibrosis in RILF by reducing M2 macrophage infiltration and inhibiting the activation of TGF\u2010\u03b21\/Smad3.<\/jats:p>","DOI":"10.1111\/jcmm.16821","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T02:55:20Z","timestamp":1627613720000},"page":"8662-8675","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":128,"title":["Pirfenidone modulates macrophage polarization and ameliorates radiation\u2010induced lung fibrosis by inhibiting the TGF\u2010\u03b21\/Smad3 pathway"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8779-7144","authenticated-orcid":false,"given":"Hangjie","family":"Ying","sequence":"first","affiliation":[{"name":"Institute of Basic Medicine and Cancer (IBMC) The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital Chinese Academy of 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