Epithelial–mesenchymal transition involved in pulmonary fibrosis induced by multi-walled carbon nanotubes via TGF-beta/Smad signaling pathway

Chen, Tian; Nie, Hongqi; Gao, Xin; Yang, Jingguo; Pu, Ji; Chen, Zhangjian; Cui, Xiaojie; Wang, Yun; Wang, Haifang

doi:10.1016/j.toxlet.2014.02.004

Cited by 99 publications

(90 citation statements)

References 51 publications

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“…Various cytokines, growth factors, and signaling pathways are involved in these events. TGF-β1 is one of the most potent fibrogenic cytokines to drive EMT, fibroblast proliferation, and myofibroblast differentiation, and then induce ECM production (Cui et al, 2011;Chen et al, 2014). Previous studies have demonstrated that TGF-β1 contributes to the progress of PQ-induced lung fibrosis (Chen C.M.…”

Section: Discussionmentioning

confidence: 99%

Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice

Shao

Luo

et al. 2015

J. Zhejiang Univ. Sci. B

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Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson's trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice

Shao

Luo

et al. 2015

J. Zhejiang Univ. Sci. B

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“…TGF-b latency binding protein 1, which facilitates the release and activation of the biologically latent form TGF-b1, is detected primarily in alveolar macrophages and epithelial cells lining honeycomb cysts in areas of advanced PF (Khalil et al, 2001). TGF-b1 signaling is partly dependent on combining and activating type I TGF-b receptor; then the postreceptor signal transducers Smad2 and Smad3 are phosphorylated, resulting in the formation of a stable complex with Smad4, which transfers into the nuclei to act as a transcriptional regulator and then induces AEC injury via promotion of changes in EMT markers (Sullivan et al, 2011;Chen et al, 2014). Therefore, strategies disrupting TGF-b1/Smad signaling undoubtedly have therapeutic potential in the clinical treatment of PF.…”

Section: Introductionmentioning

confidence: 99%

High-Mobility Group Box 1 Mediates Epithelial-to-Mesenchymal Transition in Pulmonary Fibrosis Involving Transforming Growth Factor-β1/Smad2/3 Signaling

et al. 2015

J Pharmacol Exp Ther

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Epithelial-to-mesenchymal transition (EMT) is a crucial event in the cellular origin of myofibroblasts that secrete extracellular matrix in the progression of pulmonary fibrosis (PF). Highmobility group box 1 (HMGB1) is a novel mediator of EMT. However, whether this process involves the recognized transforming growth factor-b1 (TGF-b1)/Smad signaling that also contributes to EMT in PF has not yet been elucidated. Here, we developed a model of PF induced by bleomycin (BLM) in rats and conducted several simulation experiments in A549 (human) and RLE-6TN (rat) alveolar epithelial cell (AEC) lines to unravel the role of TGF-b1/Smad2/3 signaling in HMGB1-mediated EMT. We found that the levels of serum HMGB1 and lung hydroxyproline were severely elevated after BLM administration. Moreover, the protein expression of HMGB1, TGF-b1, phosphorylated Smad2/3 (p-Smad2/3), and mesenchymal markers including a-smooth muscle actin, vimentin, and type I collagen were significantly increased with the reduced protein expression of an epithelial marker (E-cadherin) in the rat model by Western blot or immunohistochemical analysis. In addition, the uptake of both exogenous TGF-b1 and HMGB1 by AECs could induce EMT; meanwhile, HMGB1 dramatically enhanced TGF-b1 expression and triggered Smad2/3 phosphorylation. In contrast, TGF-b1 deficiency evidently ameliorated HMGB1-mediated EMT with reduced p-Smad2/3 in A549 cells. It provides new insights that HMGB1 release from injured lungs promotes AEC damage through induction of the EMT process, in which TGF-b1/Smad2/3 signaling is activated and contributes to PF. These results suggest that HMGB1 may constitute a therapeutic target for developing antifibrotic agents for abnormal lung remodeling.

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“…16 The transforming growth factor-beta (TGF-β) signaling cascade has been elaborated to be involved in CNTinduced pulmonary inflammation, epithelial-to-mesenchymal transition (EMT), and fibrogenesis. [17][18][19][20][21] Biomedical applications such as delivery of therapeutic agents and imaging diagnosis based on CNTs are carried out mainly via intravenous or subcutaneous routes. Hence, the biocompatibility and safety of CNTs introduced directly into the bloodstream or other biologic tissue should be assessed.…”

Section: Introductionmentioning

confidence: 99%