1143: Metformin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice by Suppressing Igf-1

Xiao, Huijuan; Huang, Xiaoxi; Wang, Shiyao; Liu, Zheng; Dong, Ruijuan; Song, Dingyun; Zhang, Xin; Dai, Huaping

doi:10.1097/01.ccm.0000643508.83802.5f

Cited by 20 publications

(33 citation statements)

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“…For instance, metformin was found to have anti-cancer, anti-aging and anti-oxidant effects. Recently, several studies demonstrated that metformin e ciently alleviated various pulmonary brosis, including bleomycin-, radiation-and PM2.5-induced brotic models [3,7,12,15,47]. In vitro experiments found that metformin inhibited TGF-β, especially TGF-β1, -induced broblast activation [44].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, these ndings indicate that metformin might be also an important medication against brosis. Moreover, the existing research found that metformin exhibited pleiotropic mechanisms for alleviating lung brosis, such as NOX4 inhibition [18, 40], IGF-1 suppression [47], and mTOR inactivation [37,41], and so on. In this study, our aims were to determine whether metformin exerted its effect on the activation of lung broblast by regulating AMPK and BMP9 signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Metformin is a widely used biguanide antidiabetic medication in the patients with type 2 diabetes [39], and is also an important activator of adenosine monophosphosphate-activated protein kinase (AMPK) [6, 13,27]. In animal experiments, metformin was reported to not only mitigate bleomycin-and radiationinduced lung injury and pulmonary brosis through the activation of AMPK [3,7,12,47], but also protect against ne particulate matter (PM 2.5 , aerodynamic diameter ≤ 2.5 µm)-induced lung injury and brosis through AMPK independent pathway [15]. In cellular experiments, studies found that metformin-mediated activation of AMPK inhibited transforming growth factor (TGF)-β-induced proliferation, differentiation and collagen production of lung broblasts [44].…”

Section: Introductionmentioning

confidence: 99%

“…In cellular experiments, studies found that metformin-mediated activation of AMPK inhibited transforming growth factor (TGF)-β-induced proliferation, differentiation and collagen production of lung broblasts [44]. Mechanistically, some research indicated that metformin prevented broblasts activation and lung brosis through suppressing the activity of nicotinamide adenine dinucleotide phosphate of oxidase 4 (NOX4) and oxidative stress [18,40], whereas other research found that several different factors, such as TGF-β [21], transglutaminase 2 [44], insulin-like growth factor ( IGF )-1 [47], bone morphogenetic protein (BMP)2 [20], and mammalian target of rapamicin (mTOR) [37,41], were involved in the amelioration of lung brosis mediated by AMPK and its activator metformin. It follows that the mechanism of metformin against pulmonary brosis is rather complex.…”

Section: Introductionmentioning

confidence: 99%

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Metformin Inhibits BMP9-Induced Proliferation and Differentiation of Human Lung Fibroblasts via AMPK Signaling

Chen

Wang

Sheng

et al. 2021

Preprint

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Adenosine monophosphosphate-activated protein kinase (AMPK) and its activator metformin were found to be involved in the regulation of fibroblast activation and pulmonary fibrosis. However, the regulatory mechanism has been undetermined. Recently, AMPK has been reported to exert its effect through inhibiting bone morphogenetic protein (BMP) pathway. In this study, HFL-1 cells were treated with metformin or specific AMPKα1 mutants, including constitutively activated mutant (AMPK-CA) and dominant negative mutant (AMPK-DN), combined with BMP9, and then the absorbance of these cells was measured by cell counting kit (CCK)-8 assay. The colony number of HFL-1 cells stimulated by metformin with or without BMP9 was examined by colony formation assay. The protein expressions of differentiated markers (α-smooth muscle actin, collagen I and collagen III) and the key molecules of BMP9 signaling, including activin receptor-like kinase (ALK) 1 and phosphorylated small mother against decapentaplegic (p-Smad)1/5, were also evaluated by western blot. Data revealed that BMP9 induced the proliferation and differentiation of HFL-1 cells which was suppressed by metformin or AMPK-CA. Meanwhile, the effect of metformin on BMP9-induced activation was counteracted by AMPK-DN. In addition, we found that the expressions of ALK1 and p-Smad1/5 induced by BMP9 were attenuated by metformin and AMPK-CA, whereas the inhibitory responses of metformin to the increased ALK1 and p-Smad1/5 were reduced by AMPK-DN. Accordingly, these results suggested that metformin mitigated BMP9-induced proliferation and differentiation of HFL-1 cells, which was achieved partly through the activation of AMPK and inhibition of ALK1/Smad1/5 signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin Inhibits BMP9-Induced Proliferation and Differentiation of Human Lung Fibroblasts via AMPK Signaling

Chen

Wang

Sheng

et al. 2021

Preprint

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“…Metformin has been acted in other pathologies like cancer, non-alcoholic fatty liver disease, asthma, heart failure, obesity, brotic diseases, etc., with varying degrees of effect [21][22][23][24][25]. It is interesting to note that metformin exerts protective effects in various lung diseases by inhibiting in ammation, attenuating oxidative stress, and altering broblast-to-myo broblast transition [26,27]. Moreover, it has been reported that metformin could reverse established pulmonary brosis in the bleomycin-induced mouse lung brosis model [28] and low prevalence of pneumoconiosis in diabetic coal-miners [29].…”

Section: Introductionmentioning

confidence: 99%

Metformin Attenuates Silica-induced Pulmonary Fibrosis via AMPK Signaling

Cheng

Wang

et al. 2021

Preprint

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Background: Silicosis is one of the most common occupational pulmonary fibrosis caused by respirable silica-based particle exposure, with no ideal drugs at present. Metformin, a commonly used biguanide antidiabetic agent, could activate AMP-activated protein kinase (AMPK) to exert its pharmacological action. Therefore, we sought to investigate the role of metformin in silica-induced lung fibrosis.Methods: The anti-fibrotic role of metformin was assessed in 50 mg/kg silica-induced lung fibrosis model. SiO2-stimulated lung epithelial cells/macrophages and TGF-β-induced differentiated lung fibroblasts were used for in vitro models.Results: At the concentration of 300 mg/kg in the mouse model, metformin significantly reduced lung inflammation and fibrosis in SiO2-instilled mice at the early and late fibrotic stages. Besides, metformin (range 2mM to 10mM) reversed SiO2-induced cell toxicity, oxidative stress, and epithelial-mesenchymal transition process in epithelial cells (A549 and HBE), inhibited inflammation response in macrophages (THP-1), and alleviated TGF-β1-stimulated fibroblast activation in lung fibroblasts (MRC-5) via an AMPK-dependent pathway.Conclusions: In this study, we identified that metformin might be a potential drug for silicosis treatment.

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Integrated multicomponent analysis based on UHPLC‐Q‐Exactive Orbitrap‐MS and network pharmacology to elucidate the potential mechanism of Baoyuan decoction against idiopathic pulmonary fibrosis

Zhang

Gao

et al. 2022

Phytochemical Analysis

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Introduction: Idiopathic pulmonary fibrosis (IPF) is a serious lung disease with a high mortality rate. Baoyuan decoction (BYD), a classic medicinal food homology recipe, has anti-apoptotic effects, enhances immune function, and alleviates fibrosis, suggesting that it may be a potential therapeutic drug for IPF.Objectives: We aimed to identify the main active ingredients of BYD, determine the basis of its efficacy, prove its anti-IPF effects, and explore the mechanisms underlying its anti-IPF effects. Materials and methods:In this study, the active components of BYD were detected and analysed by ultra-high-performance liquid chromatography coupled with hybrid quadrupole Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS). A network pharmacology analysis was performed to determine the potential targets and relevant pathways of BYD in treating IPF. Western blotting and quantitative realtime polymerase chain reaction (qPCR) were conducted to verify the efficacy of BYD against IPF. Finally, molecular docking and qPCR were performed to identify the central targets of BYD.Results: A total of 39 components of BYD were identified. After performing the network pharmacology analysis, 35 active components and eight presumptive targets of BYD were found to play a central role in its anti-IPF effects. The molecular docking results indicated that most of the active components of BYD exhibited good binding activity with these eight central target proteins. In addition, the expression of collagen, α-SMA, and these eight targets in human pulmonary fibroblast (HPF) cells was suppressed from treatment with BYD. Conclusion:This study determined the efficacy of BYD against IPF and clarified its multiple-target and multiple-pathway mechanisms. Furthermore, the study also provides a new method for exploring the chemical and pharmacological bases of other traditional Chinese medicine (TCM).

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1143: Metformin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice by Suppressing Igf-1

Cited by 20 publications

References 0 publications

Metformin Inhibits BMP9-Induced Proliferation and Differentiation of Human Lung Fibroblasts via AMPK Signaling

Metformin Inhibits BMP9-Induced Proliferation and Differentiation of Human Lung Fibroblasts via AMPK Signaling

Metformin Attenuates Silica-induced Pulmonary Fibrosis via AMPK Signaling

Integrated multicomponent analysis based on UHPLC‐Q‐Exactive Orbitrap‐MS and network pharmacology to elucidate the potential mechanism of Baoyuan decoction against idiopathic pulmonary fibrosis

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