Calcitriol inhibits bleomycin-induced early pulmonary inflammatory response and epithelial–mesenchymal transition in mice

Tan, Zhu-Xia; Chen, Yuan-Hua; Xu, Shen; Qin, Hou-Ying; Zhang, Cheng; Zhao, Hui; D, Xu

doi:10.1016/j.toxlet.2015.10.022

Cited by 37 publications

(29 citation statements)

References 51 publications

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“…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 ]. Here, we suggested that vitamin D opposed the TGF-β-induced EMT and ECM-related genes in human alveolar epithelia cells.…”

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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“…An in vivo study demonstrated that vitamin D attenuates bleomycinevoked EMT via repressed TGF-b/Smad signaling activation (44). Vitamin D undergoes a sequential two-step metabolism in the liver and kidneys to form 1,25(OH) 2 D 3 , which is thought to be the most potent metabolite of vitamin D. Mounting evidence suggests that vitamin D represses Smad3 signaling activation through the interaction between Smad3 and VDR (45,46).…”

Section: Discussionmentioning

confidence: 99%

Low Vitamin D Status Is Associated with Epithelial–Mesenchymal Transition in Patients with Chronic Obstructive Pulmonary Disease

Fei

Cao

et al. 2019

The Journal of Immunology

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Vitamin D deficiency is correlated with the increased morbidity of chronic obstructive pulmonary disease (COPD). However, the mechanisms underlying these effects have largely remained elusive. This study analyzed the correlations among COPD, vitamin D concentration, and epithelial-mesenchymal transition (EMT). Ninety-five patients with newly diagnosed COPD and 190 age-and sex-matched healthy subjects were recruited for this research. Serum 25(OH)D levels were detected, and pulmonary EMT biomarkers and TGF-b/Smad signaling were evaluated. Serum 25(OH)D level was remarkably decreased in COPD patients compared with that in control subjects. Furthermore, serum 25(OH)D concentration gradually decreased in COPD patients ranging from grade 1-2 to 4. However, reduced expression of the epithelial biomarker E-cadherin and increased expression of the mesenchymal biomarkers vimentin and a-SMA were found in COPD patients. Mechanistic analysis showed that pulmonary nuclear vitamin D receptor (VDR) was decreased in patients with COPD. In contrast, TGF-b/Smad signaling was obviously activated in COPD patients. Furthermore, the level of serum TGF-b in COPD patients increased in parallel with COPD severity. Serum 25(OH)D concentration was inversely associated with TGF-b levels in COPD patients. In vitro experiments showed that active vitamin D3 inhibits TGF-b-induced Smad2/3 phosphorylation in MRC-5 cells. Furthermore, vitamin D concentration was inversely correlated with TGF-b/Smad signaling and EMT in COPD patients, suggesting EMT as a vital mediator of COPD development in patients with low vitamin D concentrations.

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“…One previous in vitro study demonstrated that Akt activation was enhanced by HDAC4 through the inhibition of protein phosphatase-mediated Akt dephosphorylation in the regulation of TGF-β1-mediated α-SMA expression in human lung fibroblasts [ 19 ]. Notably, Tan et al reported that Akt was involved in the pathway regulating EMT in a mouse model of bleomycin-induced lung injury [ 35 ]. Additionally, in our previous study, we demonstrated that high-V T MV augmented pulmonary fibrosis through the activation of Akt signaling using an in vivo bleomycin mouse model [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…A previous in vitro study demonstrated that Akt phosphorylation was modulated by HDAC4 in the regulation of TGF-β1-mediated α-SMA expression [ 19 ]. Additionally, Tan et al showed that Akt plays a role in regulating bleomycin-induced EMT in mice [ 35 ]. In our previous study, we demonstrated that high-V T ventilation-aggravated pulmonary fibrosis was dependent on the activation of the Akt pathway using an in vivo bleomycin mouse model [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway

Lee

Lin

et al. 2017

PLoS ONE

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BackgroundMechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can cause diffuse lung inflammation, an effect termed ventilator-induced lung injury, which may produce profound pulmonary fibrogenesis. Histone deacetylases (HDACs) and serine/threonine kinase/protein kinase B (Akt) are crucial in modulating the epithelial–mesenchymal transition (EMT) during the reparative phase of ARDS; however, the mechanisms regulating the interactions among MV, EMT, HDACs, and Akt remain unclear. We hypothesized that trichostatin A (TSA), a HDAC inhibitor, can reduce MV-augmented bleomycin-induced EMT by inhibiting the HDAC4 and Akt pathways.MethodsFive days after bleomycin treatment to mimic acute lung injury (ALI), wild-type or Akt-deficient C57BL/6 mice were exposed to low-tidal-volume (low-VT, 6 mL/kg) or high-VT (30 mL/kg) MV with room air for 5 h after receiving 2 mg/kg TSA. Nonventilated mice were examined as controls.ResultsFollowing bleomycin exposure in wild-type mice, high-VT MV induced substantial increases in microvascular leaks; matrix metalloproteinase-9 (MMP-9) and plasminogen activator inhibitor-1 proteins; free radical production; Masson’s trichrome staining; fibronectin, MMP-9, and collagen 1a1 gene expression; EMT (identified by increased localized staining of α-smooth muscle actin and decreased staining of E-cadherin); total HDAC activity; and HDAC4 and Akt activation (P < 0.05). In Akt-deficient mice, the MV-augmented lung inflammation, profibrotic mediators, EMT profiles, Akt activation, and pathological fibrotic scores were reduced and pharmacologic inhibition of HDAC4 expression was triggered by TSA (P < 0.05).ConclusionsOur data indicate that TSA treatment attenuates high-VT MV-augmented EMT after bleomycin-induced ALI, in part by inhibiting the HDAC4 and Akt pathways.

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Calcitriol inhibits bleomycin-induced early pulmonary inflammatory response and epithelial–mesenchymal transition in mice

Cited by 37 publications

References 51 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

Low Vitamin D Status Is Associated with Epithelial–Mesenchymal Transition in Patients with Chronic Obstructive Pulmonary Disease

Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway

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