Metformin in Idiopathic Pulmonary Fibrosis “Seeking the Holy-Grail through Drug-Repositioning”

Tzouvelekis, Argyrios; Tzilas, Vasilios; Dassiou, M; Bouros, Demosthenes

doi:10.1159/000490917

Cited by 7 publications

(5 citation statements)

References 15 publications

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“…The non-standard use of a drug is a method to improve treatment and understanding of the disease. Compared to traditional drug development, exploring the treatment scope of existing drugs is more convenient, cheaper, and less risky ( Jin and Wong, 2014 ; Tzouvelekis et al, 2018 ). A new function of the old drug MET, the anti-fibrotic effect, has been explored.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

Xiao

Chen

et al. 2022

Front. Pharmacol.

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Background: Pulmonary fibrosis (PF) is a lung disease with no curative drug, characterized by a progressive decrease in lung function. Metformin (MET) is a hypoglycemic agent with the advantages of high safety and low cost and has been used in several in vivo trials to treat fibrotic diseases.Objective: This study aimed to explore the efficacy and safety of MET in treating PF and elaborate on its mechanism.Methods: Eight databases were searched for in vivo animal trials of MET for PF from the time of database creation until 1 March 2022. The risk of bias quality assessment of the included studies was conducted using SYRCLE’s risk of bias assessment. Pulmonary inflammation and fibrosis scores were the primary outcomes of this study. Hydroxyproline (HYP), type I collagen (collagen I), α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), Smad, AMP-activated protein kinase (AMPK), and extracellular signal–regulated kinase (ERK) protein expression in lung tissues and animal mortality were secondary outcomes. Effect magnitudes were combined and calculated using Revman 5.3 and Stata 16.0 to assess the efficacy and safety of MET in animal models of PF. Inter-study heterogeneity was examined using the I2 or Q test, and publication bias was assessed using funnel plots and Egger’s test.Results: A total of 19 studies involving 368 animals were included, with a mean risk of bias of 5.9. The meta-analysis showed that MET significantly suppressed the level of inflammation and degree of PF in the lung tissue of the PF animal model. MET also reduced the content of HYP, collagen I, α-SMA, and TGF-β and phosphorylation levels of Smad2, Smad3, p-smad2/3/smad2/3, ERK1/2, and p-ERK1/2/ERK1/2 in lung tissues. MET also elevated AMPK/p-AMPK levels in lung tissues and significantly reduced animal mortality.Conclusion: The results of this study suggest that MET has a protective effect on lung tissues in PF animal models and may be a potential therapeutic candidate for PF treatment.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=327285, identifier CRD42022327285.

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Section: Discussionmentioning

confidence: 99%

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

Xiao

Chen

et al. 2022

Front. Pharmacol.

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“…In that study, 71 metformin users did not present improvements in clinical outcomes compared to 553 non-metformin users 51 . As pointed out by Tzouvelekis and colleagues, these data cannot be generalized into the global IPF population due to many caveats in the study design including the post-hoc nature of the study, the low number of metformin users, lack of stringent criteria for diagnosis and assessment of diabetes control, inability to link metformin mechanisms to IPF pathogenesis or to delineate drug-drug interactions 52 . Given its low cost and the fact that it is well tolerated in humans, it will be useful to test the curative effect of metformin, either alone or in combination with other antifibrotic agents, in non-diabetic IPF patients.…”

Section: Discussionmentioning

confidence: 99%

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

Kheirollahi

Wasnick

Biasin

et al. 2018

Preprint

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Idiopathic pulmonary fibrosis is a fatal, incurable lung disease in which the intricate alveolar network of the human lung is progressively replaced by fibrotic scars, eventually leading to respiratory failure. Myofibroblasts are the effector cells that lead to abnormal deposition of extracellular matrix proteins and therefore mediate fibrotic disease not only in the lung but also in other organs. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug, metformin, exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung myofibroblasts derived from human patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-tolipofibroblast transdifferentiation. Detailed pathway analysis showed that the reduction of collagen synthesis was largely AMPK-dependent, whereas the transdifferentiation of myo-to lipofibroblasts occurred in a BMP2-PPARγ-dependent fashion and was largely AMPK-independent. Our data report an unprecedented role for metformin in lung fibrosis, thus warranting further therapeutic evaluation.

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“…In experimental models of pulmonary fibrosis, metformin, an antidiabetic agent, shows a possibility of exerting anti-fibrotic activity via affecting the autophagy and cellular bioenergetics through activation of adenosine monophosphate-activated protein kinase. However, metformin failed to show a remarkable impact on major disease outcomes, in clinical trials ( Tzouvelekis et al ., 2018 ).…”

Section: Pharmacological Agents Tried For the Regulation Of Idiopathi...mentioning

confidence: 99%

Searching for Novel Candidate Small Molecules for Ameliorating Idiopathic Pulmonary Fibrosis: a Narrative Review

Kim

Hossain

et al. 2023

Biomol Ther (Seoul)

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Idiopathic pulmonary fibrosis (IPF) can be defined as a progressive chronic pulmonary disease showing scarring in the lung parenchyma, thereby resulting in increase in mortality and decrease in the quality of life. The pathophysiologic mechanism of fibrosis in IPF is still unclear. Repetitive microinjuries to alveolar epithelium with genetical predisposition and an abnormal restorative reaction accompanied by excessive deposition of collagens are involved in the pathogenesis. Although the two FDA-approved drugs, pirfenidone and nintedanib, are under use for retarding the decline in lung function of patients suffered from IPF, they are not able to improve the survival rate or quality of life. Therefore, a novel therapeutic agent acting on the major steps of the pathogenesis of disease and/or, at least, managing the clinical symptoms of IPF should be developed for the effective regulation of this incurable disease. In the present review, we tried to find a potential of managing the clinical symptoms of IPF by natural products derived from medicinal plants used for controlling the pulmonary inflammatory diseases in traditional Asian medicine. A multitude of natural products have been reported to exert an antifibrotic effect in vitro and in vivo through acting on the epithelial-mesenchymal transition pathway, transforming growth factor (TGF)-β-induced intracellular signaling, and the deposition of extracellular matrix. However, clinical antifibrotic efficacy of these natural products on IPF have not been elucidated yet. Thus, those effects should be proven by further examinations including the randomized clinical trials, in order to develop the ideal and optimal candidate for the therapeutics of IPF.

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Metformin in Idiopathic Pulmonary Fibrosis “Seeking the Holy-Grail through Drug-Repositioning”

Cited by 7 publications

References 15 publications

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: A preclinical systematic review and meta-analysis

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

Searching for Novel Candidate Small Molecules for Ameliorating Idiopathic Pulmonary Fibrosis: a Narrative Review

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