Pirfenidone modulates macrophage polarization and ameliorates radiation‐induced lung fibrosis by inhibiting the TGF‐β1/Smad3 pathway

Ying, Hangjie; Fang, Min; Hang, Qing Qing; Chen, Yamei; Xu, Qian; Chen, Ming

doi:10.1111/jcmm.16821

Cited by 50 publications

(44 citation statements)

References 52 publications

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“…Accumulating evidence has shown that the M2 polarization of macrophages contributes to the development and progression of IPF through the secretion of cytokines [ 32 ] such as TGF-β1 and CTGF [ 5 , 33 , 34 ]. For instance, pirfenidone exerts its antifibrotic property in part by suppressing the TGF-β expression relevant to macrophage M2 polarization and fibroblast activation [ 35 ]. Furthermore, Neotuberostemonine (NTS), one of the traditional Chinese medicines included in all versions of the Chinese Pharmacopoeia, can effectively attenuate BLM-induced PF by suppressing the recruitment and polarization of M2 macrophages [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Peimine ameliorates pulmonary fibrosis via the inhibition of M2-type macrophage polarization through the suppression of P38/Akt/STAT6 signals

Cai

Tian

et al. 2022

Bioscience Reports

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Peimine, a bioactive substance isolated from Chinese medicine Fritillaria, can potentially suppress pulmonary fibrosis (PF); however, its therapeutic mechanism remains unclear. Recent evidence suggests the participation of M2-type macrophages in the pathogenesis of PF. The present study aimed to investigate the effect of peimine on a bleomycin (BLM)-induced PF rat model and the underlying mechanism of this effect. After BLM administration, peimine was administered to rats from day 29 to day 42, with pirfenidone (PFD) as a positive control. H&E and Masson’s trichrome stain were used to analyze histological changes. Q-PCR and western blotting were used to measure mRNA levels and protein levels, respectively. High-throughput RNA sequencing (RNA-seq) technology detected the differentially expressed genes (DEGs) regulated by peimine. Our results revealed that peimine treatment significantly ameliorated BLM-induced PF by suppressing histological changes and collagen deposition. In addition, peimine decreased the number of M2 macrophages and the expression of profibrotic factors. RNA-seq results showed that DEGs regulated by peimine in IL-4-induced macrophages were mainly associated with immune system processes, the PI3K/Akt pathway, and the MAPKs pathway. Then, immunofluorescence assay and western blot results demonstrated that peimine treatment suppressed the expression of p-p38 MAPK and p-Akt (s473) and also inhibited the nuclear translocation of p-STAT6. In conclusion, the present study demonstrated that peimine has a protective effect on PF through the suppression of M2 polarization of macrophages by inhibiting the STAT6, p38 MAPK, and Akt signals.

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Section: Discussionmentioning

confidence: 99%

Peimine ameliorates pulmonary fibrosis via the inhibition of M2-type macrophage polarization through the suppression of P38/Akt/STAT6 signals

Cai

Tian

et al. 2022

Bioscience Reports

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“…Pirfenidone is one of the two targeted drugs approved by the US Food and Drug Administration for the treatment of IPF. Recently, Ying et al demonstrated that pirfenidone ameliorated fibrosis by attenuating M2 macrophage infiltration and inhibiting the activation of TGF‐ β 1/Smad3 pathway 27 . Guo et al demonstrated that neohesperidin inhibits TGF‐ β 1‐induced injury to alveolar epithelial cells and decreases TGF‐ β 1‐induced myofibroblast differentiation, extracellular matrix production and fibroblast migration.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of AHNAK nucleoprotein 2 alleviates pulmonary fibrosis by downregulating the TGF‐β1/Smad3 signaling pathway

Zhu

Zhang

et al. 2022

The Journal of Gene Medicine

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Background Idiopathic pulmonary fibrosis (IPF) is a chronic and advanced interstitial lung disease with poor prognosis. AHNAK nucleoprotein 2 (AHNAK2) is a macromolecular protein that is important for cell migration and muscle membrane repair. The protein acts via epithelial–mesenchymal transition (EMT), which is a key mechanism in the pathogenesis of IPF. However, very few studies have elucidated the effect of AHNAK2 in the development of IPF. Therefore, we aimed to determine the role of AHNAK2 in IPF development. Methods C57BL/6 mice were induced with bleomycin, while A549 and Beas‐2b pulmonary epithelial cell lines were treated with TGF‐β1 to induce IPF model. The expression of AHNAK2 was detected using immunohistochemistry staining in vivo, and real‐time quantitative polymerase chain reaction (RT‐qPCR) and western blotting (WB) in vitro. C57BL/6 mice were injected with adeno‐associated virus (AAV)‐sh NC or AAV‐sh AHNAK2 and the pulmonary function and EMT marker expression were measured. The migratory abilities of the two transforming growth factor beta 1 (TGF‐β1)‐induced cell lines were examined using wound‐healing and Transwell assays after transfection with si‐NC, si‐AHNAK2‐1 and ‐2. EMT marker expression was detected using RT‐qPCR and WB. Smad3 and phosphorylated‐Smad3 of the two cells were examined using WB. Following Smad3 inhibition by Smad3 phosphorylation inhibitor (SIS3), TGF‐β1‐induced cell migration and EMT marker expression were evaluated again after different transfections. Results AHNAK2 expression was higher in the IPF model than in the normal model in vivo and in vitro. Partial inhibition of AHNAK2 suppressed the EMT process and improved pulmonary ventilation and compliance in the mouse model of IPF. Similarly, knockdown of AHNAK2 suppressed the migration of pulmonary epithelial cells and reversed EMT. Furthermore, Smad3 of the two TGF‐β1‐induced cell lines was not activated when AHNAK2 was inhibited. When SIS3 inhibited the activation of Smad3, the suppression of AHNAK2 had no effect on A549 and Beas‐2b, regardless of TGF‐β1 induction. Conclusions Inhibition of AHNAK2 alleviates pulmonary fibrosis and partially reverses EMT by inhibiting the TGF‐β1/Smad3 signaling pathway. Therefore, AHNAK2 is a potential therapeutic target for IPF.

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“…Pirfenidone was found to inhibit the TGF-β-induced phosphorylation of Smad3, p38, and Akt, key factors in the TGF-β pathway 36 and to regulate macrophage polarization and reduce radiation-induced pulmonary fibrosis by inhibiting the TGF-β1/Smad3 pathway. 37 LY2109761 is a novel selective TGF-β inhibitor that inhibits on the phosphorylation of Smad2, attenuating radiation-induced pulmonary fibrosis in mice by inhibiting the TGF-β1/Smad2 pathway. 38 These results suggest that inhibiting TGF-β1 attenuates lung injury.…”

Section: Discussionmentioning

confidence: 99%

Effect of PD-1 Inhibitor Combined with X-Ray Irradiation on the Inflammatory Microenvironment and Lung Tissue Injury in Mice

Geng¹,

Su²,

Cao³

et al. 2022

JIR

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Purpose This study was designed to evaluate the effects of PD-1 inhibitor on lung tissue morphology and the immune system in a mouse model of radiation-induced lung injury (RILI) and to assess interactions between radiation therapy and PD-1 inhibition. Methods Twenty C57BL/6 mice were divided randomly into four groups of five mice each. Mice were treated with an anti-mouse PD-1 monoclonal antibody, whole thorax irradiation, both or neither. Lung tissue morphology and pathological changes were assessed by hematoxylin-eosin staining; lung fibrosis was assessed by Masson staining and analysis of hydroxyproline; CD3+, CD4+, and CD8+ T lymphocytes in lung tissues were detected immunohistochemically; and the concentrations of transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6) in lung tissue were evaluated by cytokine multiplex analysis. Results Lung injury scores and indicators of pulmonary fibrosis were higher in mice administration whole thorax irradiation than in control mice. Inflammatory infiltrate scores, alveoli deformation scores, collagen volume fractions and hydroxyproline contents in lung tissues were all significantly higher in mice administered PD-1 inhibitor plus irradiation than in the other three groups. Similarly, the percentages of CD3+ and CD8+T cells and the concentrations of IL-6 and TGF-β1 in lung tissue were significantly higher in mice treated with radiation and PD-1 inhibitor than in the other groups. However, PD-1 inhibitor and irradiation interacted significantly only in the elevation of TGF-β1 level. Conclusion Whole thorax X-ray irradiation in mice can cause pulmonary injury and fibrosis, which could be exacerbated by PD-1 inhibitors. Radiotherapy combined with PD-1 inhibitors may aggravate RILI by synergistically upregulating TGF-β1 expression, thereby affecting the immune-inflammatory microenvironment in the lungs.

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Pirfenidone modulates macrophage polarization and ameliorates radiation‐induced lung fibrosis by inhibiting the TGF‐β1/Smad3 pathway

Cited by 50 publications

References 52 publications

Peimine ameliorates pulmonary fibrosis via the inhibition of M2-type macrophage polarization through the suppression of P38/Akt/STAT6 signals

Peimine ameliorates pulmonary fibrosis via the inhibition of M2-type macrophage polarization through the suppression of P38/Akt/STAT6 signals

Inhibition of AHNAK nucleoprotein 2 alleviates pulmonary fibrosis by downregulating the TGF‐β1/Smad3 signaling pathway

Effect of PD-1 Inhibitor Combined with X-Ray Irradiation on the Inflammatory Microenvironment and Lung Tissue Injury in Mice

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