Preventive effects of vitamin D treatment on bleomycin-induced pulmonary fibrosis

Zhang, Zongmei; Yu, Xiaoting; Xia, Fang; Liang, Aibin; Zhang, Yu; Gu, Pan; Zeng, Yu; He, Jianzhong; Zhu, Hailong; Shuai, Liguo; Fan, Desheng; Han, Fei; Zhang, Lanjing; Yi, Xianghua

doi:10.1038/srep17638

Cited by 37 publications

(32 citation statements)

References 39 publications

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“…Ramirez et al demonstrated that vitamin D inhibited TGF-β-induced pro-fibrotic effects in lung fibroblasts and epithelial cells [ 33 ]. In addition, vitamin D treatment attenuated pulmonary fibrosis and associated cellular and ultra-structural changes induced by bleomycin in mice [ 38 ]. Due to the importance of inflammation and EMT in the development of pulmonary fibrosis, calcitriol can also inhibit bleomycin-induced early pulmonary inflammation and subsequent EMT in vivo [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

1α,25-dihydroxyvitamin D3 Attenuates TGF-β-Induced Pro-Fibrotic Effects in Human Lung Epithelial Cells through Inhibition of Epithelial–Mesenchymal Transition

Jiang

Yang

et al. 2017

Nutrients

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Pulmonary fibrosis is a progressive fibrotic lung disease of persisting lung injury and ineffective wound repair, with poor prognosis. Epithelial–mesenchymal transition (EMT) of alveolar epithelia cells is an early event in the development of pulmonary fibrosis, and transforming growth factor β (TGF-β) is an acknowledged inducer of EMT. Epidemiological studies demonstrated that serum levels of 25-hydroxy-vitamin D were associated with the presence of fibrosis diseases. We investigated whether vitamin D attenuated TGF-β-induced pro-fibrotic effects through inhibiting EMT in human alveolar epithelia A549 cells. A549 cells were cultured with TGF-β alone or in combination with 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). TGF-β increased the expression of the mesenchymal markers (N-cadherin and Vimentin), and decreased the expression of epithelial markers (E-cadherin). 1α,25(OH)2D3 attenuated these TGF-β-induced alterations. Furthermore, the EMT-related transcription factors (Snail and β-catenin) and the extracellular matrix genes (Collagen I and fibronectin) were inhibited by 1α,25(OH)2D3, while the expression of vitamin D receptor (VDR) was elevated. In addition, 1α,25(OH)2D3 alleviated the cell migration and the invasion abilities in TGF-β-stimulated A549 cells, determined by the scratch wound healing and transwell assays. Our findings suggested that 1α,25(OH)2D3 inhibited the pro-fibrotic phenotype of lung epithelial cells under TGF-β stimulation and provided new clues in the clinical management of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

1α,25-dihydroxyvitamin D3 Attenuates TGF-β-Induced Pro-Fibrotic Effects in Human Lung Epithelial Cells through Inhibition of Epithelial–Mesenchymal Transition

Jiang

Yang

et al. 2017

Nutrients

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“…VDR is cited as the master regulator of the genomic-driven activation of fibroblasts, although its inhibition has been suggested to re-sensitize pancreatic cancer cells that became resistant to gemcitabine [174]. In any case, VDR activation achieves stromal restoration by inhibiting the TGF-β/Smad pathway that, as previously discussed, constitutes a key driver of fibroblastic activation [125,173,175]. With the goal of ramping up the activity of VDR, investigators introduced an analog of its ligand, which resulted in the suppression of inflammatory cytokines and growth factors, enhanced angiogenesis, and increased efficacy of therapeutics while significantly improving overall survival [176].…”

Section: Restoration Of Innate Stroma Characteristics Promises a Feasmentioning

confidence: 99%

Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions

Alexander

Cukierman

2016

Current Opinion in Cell Biology

131

114

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Stromal dynamic reciprocity (SDR) consists of the biophysical and biochemical interplay between connective tissue elements that regulate and maintain organ homeostasis. In epithelial cancers, chronic alterations of SDR result in the once tumor-restrictive stroma evolving into a “new” tumor-permissive environment. This altered stroma, known as desmoplasia, is initiated and maintained by cancer associated fibroblasts (CAFs) that remodel the extracellular matrix (ECM). Desmoplasia fuels a vicious cycle of stromal dissemination enriching both CAFs and desmoplastic ECM. Targeting specific drivers of desmoplasia, such as CAFs, either enhances or halts tumor growth and progression. These conflicting effects suggest that stromal interactions are not fully understood. This review highlights known fibroblastic-ECM interactions in an effort to encourage therapies that will restore cancer-restrictive stromal cues.

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“…Vitamin D treatment could prevent bleomycin-induced pulmonary fibrosis by delaying or suppressing ultrastructural changes, as well as by attenuating hydroxyproline accumulation and inhibiting myofibroblastic proliferation 3 . Vitamin D intake decreased COPD exacerbation and improved forced expiratory volume in one second (FEV1) in patients with severe and very severe COPD 4 .…”

Section: Introductionmentioning

confidence: 99%

Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system

Shi

Liu

Yao

et al. 2017

Sci Rep

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Pulmonary fibrosis, which influences lung function and exacerbates a patient’s condition, is the ultimate stage of many lung diseases. Vitamin D deficiency is associated with pulmonary fibrosis and impaired lung function, but the underlying mechanism has not yet been fully elucidated. Moreover, vitamin D deficiency may cause over-activation of the renin-angiotensin system (RAS), which aggravates extracellular matrix (ECM) deposition and lung fibrosis. This study aims to investigate the effect of chronic vitamin D deficiency on lung fibrosis in otherwise healthy mice and to explore the role of RAS in this process. Mice were depleted of vitamin D through diet control and were compared with healthy subjects. Chronic vitamin D deficiency destructs lung structures, impairs lung development and stimulates ECM deposition. RAS components are also found to increase. These effects seem to worsen with prolonged vitamin D deficiency. By giving RAS blockers, these changes can be largely rescued. However, a smooth muscle relaxant whose regulatory effect on blood pressure is independent of RAS does not show similar effects. This study demonstrated that chronic vitamin D deficiency may induce RAS activation, which subsequently stimulates the expression of profibrotic factors and activates the fibrotic cascade. This profibrotic effect of RAS is independent of elevated blood pressure.

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Preventive effects of vitamin D treatment on bleomycin-induced pulmonary fibrosis

Cited by 37 publications

References 39 publications

1α,25-dihydroxyvitamin D3 Attenuates TGF-β-Induced Pro-Fibrotic Effects in Human Lung Epithelial Cells through Inhibition of Epithelial–Mesenchymal Transition

1α,25-dihydroxyvitamin D3 Attenuates TGF-β-Induced Pro-Fibrotic Effects in Human Lung Epithelial Cells through Inhibition of Epithelial–Mesenchymal Transition

Stromal dynamic reciprocity in cancer: intricacies of fibroblastic-ECM interactions

Chronic vitamin D deficiency induces lung fibrosis through activation of the renin-angiotensin system

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