Abstract
Radiation‐induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy. RILI can be divided into radiation pneumonia (RP) and radiation‐induced 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)‐approved drug for (IPF) treatment, and its mechanism in the treatment of RILF. In vivo, C57BL/6 mice received a 50 Gy dose of X‐ray 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‐β1 (TGF‐β1)/Drosophila mothers against the decapentaplegic 3 (Smad3) signalling pathway. Moreover, PFD treatment decreased the radiation‐induced expression of TGF‐β1 and phosphorylation of Smad3 in alveolar epithelial cells (AECs) and vascular endothelial cells (VECs). Furthermore, IL‐4–induced M2 macrophage polarization and IL‐13–induced M2 macrophage polarization were suppressed by PFD treatment in vitro, resulting in reductions in the release of arginase‐1 (ARG‐1), chitinase 3‐like 3 (YM‐1) and TGF‐β1. Notably, the PFD‐induced inhibitory effects on M2 macrophage polarization were associated with downregulation of nuclear factor kappa‐B (NF‐κB) p50 activity. Additionally, PFD could significantly inhibit ionizing radiation‐induced chemokine secretion in MLE‐12 cells and consequently impair the migration of RAW264.7 cells. PFD could also eliminate TGF‐β1 from M2 macrophages by attenuating the activation of TGF‐β1/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‐β1/Smad3.
Highlights
Radiation-induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy
Results: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 factorβ1(TGF-β1) /drosophila mothers against decapentaplegic 3 (Smad3) signaling pathway
IL-4- and IL13-induced M2 macrophage polarization was suppressed by PFD treatment in vitro, resulting in reductions in the release of arginase-1(ARG-1), chitinase 3-like 3 (YM-1) and TGF-β1
Summary
Radiation-induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy. RILI can be divided into early-stage radiation pneumonia (RP) and late-stage radiationinduced lung fibrosis (RILF). Once RILF occurs, patients will eventually develop irreversible respiratory failure; a new treatment strategy to prevent RILI is urgently needed. Clinical data show that the incidence of RILI is 5-25% after radiation therapy in patients with lung cancer, followed by those with mediastinal lymphoma (5-10%) and breast cancer (1-5%) [5]. There are two clinical manifestations of RILI: early radiation pneumonia (RP) and late radiation-induced lung fibrosis (RILF). Corticosteroids are mainly used to control early inflammation in the clinic, while RILF leads to progressive alveolar structural disorders and irreversible pulmonary fibrous tissue remodeling, which eventually causes respiratory failure. There is currently no effective drug available to reverse RILF [6]
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