Protective Role of Nuclear Factor-Erythroid 2-Related Factor 2 Against Radiation-Induced Lung Injury and Inflammation

Tian, Xiaoli; Wang, Feng; Luo, Yuan; Ma, Shijing; Zhang, Nannan; Sun, Yan; You, Chengcheng; Tang, Guping; Li, Shuying; Gong, Yan; Xie, Conghua

doi:10.3389/fonc.2018.00542

Cited by 23 publications

(14 citation statements)

References 25 publications

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“…When intracellular ROS is excessive, the endogenous Nrf2 signaling pathway will be activated. In the radiation-induced lung injury, the radiation not only reduced excessive accumulation of ROS, but also inhibited the over express of endogenous Nrf2 signaling pathway [38]. Our study also found that in RILF, the ROS levels was increased than the control group (Fig.…”

Section: Discussionsupporting

confidence: 68%

Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1

et al. 2019

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Background Radiation-induced lung fibrosis (RILF) is a severe and life-threatening complication of thoracic radiotherapy. Cell death is the key issue in RILF. Ferroptosis is a form programmed cell death implicated in the pathologies of inflammation. This study aimed to investigate the role of ferroptosis in RILF, and the effectiveness and the potential underlying mechanism of ferroptosis inhibitor on RILF. Methods Immunofluorescence, western blot and RT-PCR assays were performed to examine the ferroptosis maker glutathione peroxidase 4 (GPX4) in a mice RILF model. The lung tissue sections were stained with hematoxylin and eosin (H&E), Masson trichrome staining and Sirius-Red staining to evaluate the histopathological changes in RILF mice. Reactive oxygen species (ROS) and hydroxyproline (HYP) in lungs were measured by the relevant kits. The serum levels of inflammatory cytokines (TNF-α, IL-6, IL-10, and TGF-β1) were measured with Elisa. The protein and mRNA levels of GPX4, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hemeoxygenase-1 (HO1) and quinone oxidoreductase 1 (NQO1) in lungs were examined by western blot and RT-PCR. Results GPX4 levels of the irradiated lungs were significantly down-regulated than the groups with no irradiation, and the ferroptosis inhibitor, liproxstatin-1, increased GPX4 levels significantly in RILF mice. Treatment with liproxstatin-1 lowered the Szapiel and Ashcroft scores significantly, down-regulated the levels of ROS and HYP in lungs and reduced the serum inflammatory cytokines levels in RILF mice. The protein and the mRNA levels of Nrf2, HO1 and NQO1 were up-regulated by liproxsratin-1 in RILF. Conclusions Our data suggested that ferroptosis played a critical role in RILF, ferroptosis inhibitor liproxstatin-1 alleviated RILF via down-regulation of TGF-β1 by the activation of Nrf2 pathway. The effectiveness of ferroptosis inhibition on RILF provides a novel therapeutic target for RILF.

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Section: Discussionsupporting

confidence: 68%

Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1

et al. 2019

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“…In lung cancer, it was proven in vitro that A549 cells transfected with Nrf2siRNA were more prone to cell death as a response to radiotherapy than the control A549 cells [158]. At the same time, as Tian et al pointed out, it should be considered that Nrf2 also protects healthy cells from radiation-induced inflammation and a rise in oxidative stress [159]. The radiotherapy action is mediated mainly by enhancing the intracellular oxidative stress.…”

Section: Examples Of Nrf2 Application In Evaluating Therapy Responsementioning

confidence: 99%

The Role of Nrf2 Activity in Cancer Development and Progression

Zimța

Cenariu

Irimie

et al. 2019

Cancers

206

135

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Nrf2 is a transcription factor that stimulates the expression of genes which have antioxidant response element-like sequences in their promoter. Nrf2 is a cellular protector, and this principle applies to both normal cells and malignant cells. While healthy cells are protected from DNA damage induced by reactive oxygen species, malignant cells are defended against chemo- or radiotherapy. Through our literature search, we found that Nrf2 activates several oncogenes unrelated to the antioxidant activity, such as Matrix metallopeptidase 9 (MMP-9), B-cell lymphoma 2 (BCL-2), B-cell lymphoma-extra large (BCL-xL), Tumour Necrosis Factor α (TNF-α), and Vascular endothelial growth factor A (VEGF-A). We also did a brief analysis of The Cancer Genome Atlas (TCGA) data of lung adenocarcinoma concerning the effects of radiation therapy and found that the therapy-induced Nrf2 activation is not universal. For instance, in the case of recurrent disease and radiotherapy, we observed that, for the majority of Nrf2-targeted genes, there is no change in expression level. This proves that the universal, axiomatic rationale that Nrf2 is activated as a response to chemo- and radiation therapy is wrong, and that each scenario should be carefully evaluated with the help of Nrf2-targeted genes. Moreover, there were nine genes involved in lipid peroxidation, which showed underexpression in the case of new radiation therapy: ADH1A, ALDH3A1, ALDH3A2, ADH1B, GPX2, ADH1C, ALDH6A1, AKR1C3, and NQO1. This may relate to the fact that, while some studies reported the co-activation of Nrf2 and other oncogenic signaling pathways such as Phosphoinositide 3-kinases (PI3K), mitogen-activated protein kinase (MAPK), and Notch1, other reported the inverse correlation between Nrf2 and the tumor-promoter Transcription Factor (TF), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Lastly, Nrf2 establishes its activity through interactions at multiple levels with various microRNAs. MiR-155, miR-144, miR-28, miR-365-1, miR-93, miR-153, miR-27a, miR-142, miR-29-b1, miR-340, and miR-34a, either through direct repression of Nrf2 messenger RNA (mRNA) in a Kelch-like ECH-associated protein 1 (Keap1)-independent manner or by enhancing the Keap1 cellular level, inhibit the Nrf2 activity. Keap1–Nrf2 interaction leads to the repression of miR-181c, which is involved in the Nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling pathway. Nrf2’s role in cancer prevention, diagnosis, prognosis, and therapy is still in its infancy, and the future strategic planning of Nrf2-based oncological approaches should also consider the complex interaction between Nrf2 and its various activators and inhibitors.

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“…In RILI patients and animal model, the secretion of proinflammatory factors is closely related to polarization of lung macrophages ( 11 ). Previous reports have demonstrated that a number of important macrophage M1 polarization markers, including IL-12p35 and TNF-α, are miR-21 targets in vitro ( 12 , 13 ).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-21 mediates bone marrow mesenchymal stem cells protection of radiation-induced lung injury during the acute phase by regulating polarization of alveolar macrophages

Bao¹,

Zhao²,

Mou³

et al. 2020

Transl Cancer Res TCR

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Background Radiation-induced lung injury (RILI) often occurs in patients with non-small cell lung cancer (NSCLC) after radiotherapy, and the prognosis of patients with RILI is usually poor. This work plan to investigate the expression patterns of microRNA-21(miR-21) in NSCLC patients with RILI and the protective effects of miR-21 over-expressed bone marrow mesenchymal stem cells (BMSCs) against RILI in rat model. Methods MiR-21 expressions were determined in both serum samples and bronchoalveolar lavage fluid (BALF) samples from NSCLC patients after radiation therapy. The correlation between miR-21 expression and the follow-up clinical characterizations were determined. Further, miR-21 over-expressed BMSCs were transplanted into RILI rats and the protective effects were evaluated. BMSCs and alveolar macrophages (AMs) were co-cultured in vitro and the macrophage M1 polarization markers were determined by ELISA and qRT-PCR assays. Results Expression of miR-21 was significantly increased in NSCLC patients with RILI compared with control group, especially before or at 4 weeks after radiation therapy commenced. The miR-21 levels were highly correlated with IL-12, TNF-α, and IL-6 expressions and the severity of RILI. Animal based experiments demonstrated that BMSCs treatment had a remarkable effect on alleviating alveolitis in RILI rats, and miR-21 over-expression could enhance this effect significantly. Cell based experiments demonstrated that BMSCs notably inhibited M1 polarization of AMs and this inhibition is in a miR-21 dependent manner. Conclusions These results indicated that BMSCs could blocked the proinflammatory pathway of macrophage through miR-21 over-expression, thus could be a potential therapeutic strategy for RILI.

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Protective Role of Nuclear Factor-Erythroid 2-Related Factor 2 Against Radiation-Induced Lung Injury and Inflammation

Cited by 23 publications

References 25 publications

Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1

Ferroptosis inhibitor alleviates Radiation-induced lung fibrosis (RILF) via down-regulation of TGF-β1

The Role of Nrf2 Activity in Cancer Development and Progression

MicroRNA-21 mediates bone marrow mesenchymal stem cells protection of radiation-induced lung injury during the acute phase by regulating polarization of alveolar macrophages

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