Pirfenidone Modulates Macrophage Polarization and Ameliorates Radiation-induced Lung Fibrosis by Inhibiting the TGF-β1/Smad3 Pathway

Abstract

Background：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 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 idiopathic pulmonary fibrosis (IPF) treatment, and its mechanism in the treatment of RILF. Methods：A series of in vitro and in vivo assays were performed to explore the role and mechanism of PFD in the prevention and treatment of RILF. 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 factor-β1(TGF-β1) /drosophila mothers against decapentaplegic 3 (Smad3) signaling 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- 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. 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. 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.

The up-regulation of TGF-β1 by miRNA-132-3p/WT1 is involved in inducing leukemia cells to differentiate into macrophages

“…For example, the upstream genes or transcription regulatory proteins that regulate the expression of miRNA-132-3p need to be identified, and the manner in which TGF-β1 regulates its downstream target genes (and its complete role in performing this function) still needs to be explored. Secondly, given that it is typically encountered as the downstream gene of the TGF-β1 signaling pathway (65,66), the role of the Smad family in inducing differentiation of leukemia cells into macrophages needs to be elucidated. In addition, in order to clarify the changes observed in these three genes, and the significance of the signaling axis that they regulate, the required in vivo animal studies and the detection of primary leukemia cells in clinical patients will be important aspects of our subsequent experiments.…”

Research Progress on Pathogenesis of Idiopathic Pulmonary Fibrosis Complicated with Lung Cancer

“…Macrophages are highly plastic and their functional phenotype depends on different microenvironments, with M2 macrophages being the most prominent macrophage type in pulmonary fibrosis. Pirfenidone regulates macrophage polarization and improves radiation-induced pulmonary fibrosis by inhibiting the TGF-β1/Smad3 pathway [18].M2 macrophages are widely believed to be trigger cells for tumor progress [19]. Myeloid derived suppressor cells (MDSCs) are most commonly used to describe cells produced during chronic inflammation, especially advanced cancer, and are defined by their T cell immunosuppressive function [20].…”