BMP-7 attenuated silica-induced pulmonary fibrosis through modulation of the balance between TGF-β/Smad and BMP-7/Smad signaling pathway

Liang, Dan; Wang, Yan; Zhu, Zhaohui; Yang, Gui-Zhen; An, Guoliang; Li, Xiaoli; Niu, Piye; Chen, Li; Lin, Tian

doi:10.1016/j.cbi.2015.11.012

Cited by 54 publications

(31 citation statements)

References 26 publications

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“…Particularly, it was determined that left ventricular LV remodeling in patients with aortic stenosis as well as mice with aortic constriction involved impaired BMP/Smad 1/5/8 signaling and increased TGF/Smad2/3 pathways; and that exogenous supplementation with BMP7 reduced LV disease in the mice (Merino et al, 2016). In models of lung disease, similar opposing actions of BMP7 on TGF-β/Smad signaling were indicated by reduced p-Smad 2/3 levels and attenuation of silica-induced pulmonary fibrosis in animals treated with recombinant BMP7 (Yang et al, 2013; Liang et al, 2016). Overall, the importance of BMP7 as an antagonist to profibrogenic TGF-β/Smad signaling has been demonstrated in multiple organ model systems providing support for further investigations into the clinical efficacy of BMP7 treatment strategies.…”

Section: The Antifibrotic Therapeutic Role Of Bmp7mentioning

confidence: 90%

Novel Anti-fibrotic Therapies

McVicker

Bennett

2017

Front. Pharmacol.

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Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Novel treatments have recently been identified that hold promise as potential therapeutic agents for cardiovascular diseases associated with fibrosis, as well as other fibrotic conditions. The purpose of this review is to provide an overview of emerging antifibrotic agents that have shown encouraging results in preclinical or early clinical studies, but have not yet been approved for use in human disease. One of these agents is bone morphogenetic protein-7 (BMP7), which has beneficial effects in multiple models of fibrotic disease. Another approach discussed involves altering the levels of micro-RNA (miR) species, including miR-29 and miR-101, which regulate the expression of fibrosis-related gene targets. Further, the antifibrotic potential of agonists of the peroxisome proliferator-activated receptors will be discussed. Finally, evidence will be reviewed in support of the polypeptide hormone relaxin. Relaxin is long known for its extracellular remodeling properties in pregnancy, and is rapidly emerging as an effective antifibrotic agent in a number of organ systems. Moreover, relaxin has potent vascular and renal effects that make it a particularly attractive approach for the treatment of cardiovascular diseases. In each case, the mechanism of action and the applicability to various fibrotic diseases will be discussed.

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Section: The Antifibrotic Therapeutic Role Of Bmp7mentioning

confidence: 90%

Novel Anti-fibrotic Therapies

McVicker

Bennett

2017

Front. Pharmacol.

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“…TGF-β binds to the TGF-βI and TGF-βII receptors, activating threonine/serine kinase and promoting Smad2/3 phosphorylation, which then enhances the combination with Smad4. The Smad2/3/4 complex moves to the nucleus and increases the transcription of extracellular matrix genes, thereby enhancing collagen and fibronectin synthesis in the extracellular matrix and promoting the development of pulmonary fibrosis [20, 21]. This study showed that in the patient group, the Smad3 gene was abnormally hypomethylated compared with its status in the negative control group, Smad3 mRNA was highly expressed, and TGF-β levels in blood serum and alveolar lavage fluid were elevated.…”

Section: Discussionmentioning

confidence: 99%

The correlation between pulmonary fibrosis and methylation of peripheral Smad3 in cases of pigeon breeder’s lung in a Chinese Uygur population

Ding

Li³

et al. 2017

Oncotarget

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Smad3 is a key protein in the transforming growth factor-beta (TGF-β)/Smad signaling pathway, which is involved in fibrosis in many organs. We investigated the relationship between Smad3 gene methylation and pulmonary fibrosis in pigeon breeder's lung (PBL). Twenty Uygur PBL patients with pulmonary fibrosis in Kashi between October 2015 and March 2016 were enrolled. Twenty PBL-free pigeon breeders and 20 healthy non-pigeon breeders enrolled during the same period constituted the negative and normal control groups, respectively. Participants’ data and peripheral blood samples were collected, and three Smad3 CpG loci were examined. Distributions of CpG_2 and CpG_4 methylation rates did not differ across groups, whereas distributions of CpG_3 methylation rates were significantly different among the three groups. The CpG_3 methylation rate was significantly lower in the patient group than in the negative control group. Smad3 mRNA expression was significantly higher in the patient group than in the negative control group but did not differ between the two control groups. TGF-βlevels were significantly higher in the patient group than in either control group (both P<0.01). Smad3 gene methylation and Smad3 mRNA expression were negatively correlated, with a correlation coefficient of -0.84. The number of pigeons bred during the preceding three months was positively correlated with Smad3 mRNA expression, with a correlation coefficient of 0.77. Smad3 gene hypomethylation might promote pulmonary fibrosis in Uygur PBL patients via increased Smad3 mRNA expression. Smad3 methylation, Smad3 mRNA expression and TGF-β level were correlated with the number of pigeons bred by patients.

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“…TGF-b/Smad signaling pathway is reported to be involved in pulmonary brosis. 22 Therefore, we investigated relative protein level of Smad2, Smad3 which were key proteins in TGF-b/Smad signaling pathway and their phosphorylation level. The data indicated that TGF-b increased the level of TGF-b and the ratios of p-Smad2/Smad2 and p-Smad3/Smad3, suggesting that TGFb activated TGF-b/Smad signaling pathway during pulmonary brosis.…”

Section: Pd Suppresses Tgf-b/smad Signaling Pathway In Pulmonary Brosismentioning

confidence: 99%

Polydatin ameliorates pulmonary fibrosis by suppressing inflammation and the epithelial mesenchymal transition via inhibiting the TGF-β/Smad signaling pathway

Qiu

Pan

2019

RSC Adv.

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Pulmonary fibrosis is a chronic and progressive lung disease which results in a loss of pulmonary function and eventually respiratory failure. Inflammation and epithelial mesenchymal transition (EMT) play important roles in the pathogenesis of pulmonary fibrosis. This study aimed to investigate the therapeutic effect of polydatin (PD) in bleomycin-induced pulmonary fibrosis. A bleomycin-induced pulmonary fibrosis animal model used SD rats. Morphological changes were analyzed by hematoxylin-eosin staining. RT-qPCR and western blot were used for the detection of the expression of TGF-b1, collagen I, collagen III, Ecadherin, fibronectin and the ratios of p-Smad2/Smad2, p-Smad3/Smad3. The concentrations of PICP, PIIINP, TNF-a, IL-1b, IL-6 and IL-17 were measured by enzyme linked immunosorbent assay (Elisa) assay. Results showed that PD attenuated bleomycin-induced pulmonary fibrosis. The beneficial effect of PD was possibly related to the inhibition of inflammation and EMT through suppressing the TGF-b/Smad signaling pathway. Our findings suggested that PD might be a potential therapeutic candidate in the treatment of pulmonary fibrosis.Fig. 4 PD suppresses TGF-b/Smad signaling pathway in pulmonary fibrosis. (A) Relative protein level of TGF-b, p-Smad2, Smad2, p-Smad3, Smad3 was detected by Western blot. (B-D) The ratios of TGF-b, p-Smad2/Smad2 and p-Smad3/Smad3 in different groups. All data were represented as the mean AE SD from three independent experiments. **P < 0.01 compared with control group, # P < 0.05, ## P < 0.01 compared with TGF-b group.8110 | RSC Adv., 2019,9,[8104][8105][8106][8107][8108][8109][8110][8111][8112] This journal is

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BMP-7 attenuated silica-induced pulmonary fibrosis through modulation of the balance between TGF-β/Smad and BMP-7/Smad signaling pathway

Cited by 54 publications

References 26 publications

Novel Anti-fibrotic Therapies

Novel Anti-fibrotic Therapies

The correlation between pulmonary fibrosis and methylation of peripheral Smad3 in cases of pigeon breeder’s lung in a Chinese Uygur population

Polydatin ameliorates pulmonary fibrosis by suppressing inflammation and the epithelial mesenchymal transition via inhibiting the TGF-β/Smad signaling pathway

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