Pirfenidone suppresses polarization to M2 phenotype macrophages and the fibrogenic activity of rat lung fibroblasts

Toda, Magdalena; Mizuguchi, Shinjiro; Minamiyama, Yukiko; Yamamoto-Oka, Hiroko; Aota, Takanori; Kubo, Shoji; Nishiyama, Noritoshi; Shibata, Toshihiko; Takemura, Shigekazu

doi:10.3164/jcbn.17-111

Cited by 37 publications

(36 citation statements)

References 34 publications

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“…We con rmed that macrophages cultured with IL-4 and IL-13 secreted high levels of TGF-β1, while PFD could signi cantly inhibit the expression of TGF-β1 by M2 macrophages, which was consistent with the ndings of Toda M et al [50] . AECs can activate broblasts through epithelial-mesenchymal transition (EMT) and then differentiate into myo broblasts, which form characteristic broblast foci and secrete ECM, leading to brosis.…”

Section: Discussionsupporting

confidence: 90%

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

Ying

Fang

Hang

et al. 2020

Preprint

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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.

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Section: Discussionsupporting

confidence: 90%

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

Ying

Fang

Hang

et al. 2020

Preprint

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“…Note that macrophages are ubiquitous innate immune cells and can be polarized in two distinct functional phenotypes, either in pro-inflammatory macrophages called M1 or in M2 macrophages that promote immune suppression and wound healing [88][89][90]. They also suggest a preferential differentiation in M2 macrophages in vivo compared to M1 that were found in vitro and in ALI conditions.…”

Section: Transcriptomic Studymentioning

confidence: 95%

Toxicity of TiO2 Nanoparticles: Validation of Alternative Models

Leroux

Doumandji

Chézeau

et al. 2020

IJMS

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There are many studies concerning titanium dioxide (TiO2) nanoparticles (NP) toxicity. Nevertheless, there are few publications comparing in vitro and in vivo exposure, and even less comparing air–liquid interface exposure (ALI) with other in vitro and in vivo exposures. The identification and validation of common markers under different exposure conditions are relevant for the development of smart and quick nanotoxicity tests. In this work, cell viability was assessed in vitro by WST-1 and LDH assays after the exposure of NR8383 cells to TiO2 NP sample. To evaluate in vitro gene expression profile, NR8383 cells were exposed to TiO2 NP during 4 h at 3 cm2 of TiO2 NP/cm2 of cells or 19 μg/mL, in two settings—submerged cultures and ALI. For the in vivo study, Fischer 344 rats were exposed by inhalation to a nanostructured aerosol at a concentration of 10 mg/m3, 6 h/day, 5 days/week for 4 weeks. This was followed immediately by gene expression analysis. The results showed a low cytotoxic potential of TiO2 NP on NR8383 cells. Despite the absence of toxicity at the doses studied, the different exposures to TiO2 NP induce 18 common differentially expressed genes (DEG) which are involved in mitosis regulation, cell proliferation and apoptosis and inflammation transport of membrane proteins. Among these genes, we noticed the upregulation of Ccl4, Osm, Ccl7 and Bcl3 genes which could be suggested as early response biomarkers after exposure to TiO2 NP. On the other hand, the comparison of the three models helped us to validate the alternative ones, namely submerged and ALI approaches.

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“…To examine the expression of LOX in monocytic THP-1 cell-derived M2-like macrophages, we initially investigated the expression of the M2-like macrophages differentiation markers, arginase-1 and CD206. (20) THP-1 cell-derived M2-like macrophages were prepared by the treatment with TPA for 24 h (M0 macrophages), and a subsequent treatment with IL-4 and IL-13 for the indicated times. As shown in Fig.…”

Section: Confirmation Of Thp 1 Cell Differentiation Into M2 Likementioning

confidence: 99%

Lysyl oxidase expression is regulated by the H3K27 demethylase Jmjd3 in tumor-associated M2-like macrophages

Takemoto

Kamiya

Hara

et al. 2020

J. Clin. Biochem. Nutr.

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Copper is one of the essential micronutrients, and copper containing enzymes contribute to crucial functions in the body. Lysyl oxidase is a copper containing enzyme that remodels the extracellular matrix by cross linking collagen and elastin. The overexpression of lysyl oxidase was recently shown to promote tumor metastasis. M2 like macrophages were also found to significantly accumulate in the tumor microenvironment, and correlated with a poor patient's outcome. We speculate that M2 like macrophages promote tumor progression via lysyl oxidase expression. Epigenetics, a mitotically heritable change in gene expression without any change in DNA sequencing, is also associated with tumor progression. However, the relationship between lysyl oxidase expression in M2 like macrophages and epigenetics remains unclear. Lysyl oxidase expression was significantly induced in human leukemic THP 1 cell derived M2 like macrophages. Furthermore, the level of histone H3 tri methylation at lysine 27 was decreased, and a pre treatment with a H3K27 demethylase inhibitor notably suppressed lysyl oxidase expression in M2 like macrophages. Lysyl oxidase derived from M2 like macrophages also enhanced breast cancer cell migra tion, and this was suppressed by a H3K27 demethylase inhibitor. The present results suggest the mechanism of lysyl oxidase expression in M2 like macrophages as an aspect of epigenetics, particularly histone methylation.

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Pirfenidone suppresses polarization to M2 phenotype macrophages and the fibrogenic activity of rat lung fibroblasts

Cited by 37 publications

References 34 publications

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

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

Toxicity of TiO2 Nanoparticles: Validation of Alternative Models

Lysyl oxidase expression is regulated by the H3K27 demethylase Jmjd3 in tumor-associated M2-like macrophages

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