Metformin Regulates Alveolar Macrophage Polarization to Protect Against Acute Lung Injury in Rats Caused by Paraquat Poisoning

Yuan, Ding; Li, Yang; Hou, Linlin; Yang, Fang; Meng, Cuicui; Yu, Yanxia; Sun, Chien-Wen; Duan, Guoyu; Xu, Zhigao; Zhu, Guorong; Guo, Jianjun; Zhang, Leilei; Yan, Gai-Qin; Chen, Jihong; Yang, Yue; Zhang, Yan; Gao, Yanxia

doi:10.3389/fphar.2022.811372

Cited by 4 publications

(4 citation statements)

References 33 publications

(34 reference statements)

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“…Then, we screened, reviewed, and excluded most of these articles as not meeting our criteria stated in the method section. Finally, we included 15 preclinical studies ( Zmijewski et al, 2008 ; Jian et al, 2013 ; Liu et al, 2016 ; Vaez et al, 2016 ; Wang et al, 2016 ; Ghavimi et al, 2018 ; Wu et al, 2018 ; Yu et al, 2018 ; He et al, 2019 ; Wu et al, 2019 ; Xian et al, 2021 ; Zhang Y. et al, 2022 ; Zhang M. et al, 2022 ; Yuan et al, 2022 ; Wan et al, 2023 ) in this meta-analysis. The procedure for study selection is presented in a flow chart in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

“…As metformin has shown its role in reducing mortality in septic patients ( Li et al, 2021 ; Gómez et al, 2022 ), it is possible that metformin may also benefit ARDS. A number of preclinical studies have highlighted the effect of metformin on acute lung injury (ALI), a mild form of ARDS ( Wu et al, 2019 ; Medeiros et al, 2021 ; Xian et al, 2021 ; Yuan et al, 2022 ). Reduced mortality, pulmonary wet-to-dry weight ratio (W/D), lung injury scores, protein in bronchoalveolar lavage fluid, and levels of malondialdehyde (MDA) as well as myeloperoxidase (MPO) in the lungs were announced in those studies.…”

Section: Introductionmentioning

confidence: 99%

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Effects of metformin on acute respiratory distress syndrome in preclinical studies: a systematic review and meta-analysis

Wang,

Tian,

Deng

2023

Front. Pharmacol.

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Introduction: In this study, we conducted a systematic review and meta-analysis to judge the effects of metformin on acute respiratory distress syndrome (ARDS) in a comprehensive and quantitative manner.Methods: We included studies that tested the effects of metformin on ALI or ARDS in in vivo studies. We excluded literature from which data could not be extracted or obtained. Electronic search was conducted to retrieve relevant literature from public databases, including PubMed, Web of Science, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (inception to July 2023). Moreover, ProQuest Dissertations and Theses Global, Google Scholar, and Baidu scholar were inquired. Retrieved literature was screened and evaluated by pairs of reviewers independently according to pre-stated criteria. The Systematic Review Center for Laboratory Animal Experimentation risk of bias tool was used to evaluate the methodological quality of eligible literature. No restriction was exerted on publication status or language.Results: Fifteen preclinical studies were analyzed in this meta-analysis. Pooled results showed metformin effectively decreased pulmonary wet-to-dry weight ratios [SMD = −2.67 (−3.53 to −1.81), I2 = 56.6%], protein content [SMD = −3.74 (−6.76 to −0.72), I2 = 86.7%] and neutrophils [SMD = −3.47 (−4.69 to −2.26), I2 = 0%] in BALF, pulmonary malondialdehyde [SMD = −1.98 (−3.77 to −0.20), I2 = 74.2%] and myeloperoxidase activity [SMD = −3.15 (−4.79 to −1.52), I2 = 74.5%], lung injury scores [SMD = −4.19 (−5.65 to −2.74), I2 = 69.1%], and mortality at 24 h [RR = 0.43 (0.24–0.76), I2 = 0%] as well as 48 and 72 h.Conclusion: Metformin inhibited pulmonary inflammation and oxidative stress and improved experimental lung injury and survival rates in animal models of ARDS. Results from randomized controlled trials are needed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of metformin on acute respiratory distress syndrome in preclinical studies: a systematic review and meta-analysis

Wang,

Tian,

Deng

2023

Front. Pharmacol.

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“…This study also highlighted the protective effect of metformin in SARS-CoV-2 induced pulmonary inflammation in hACE2 transgenic mice. Furthermore, metformin treatment alleviated paraquet-induced lung inflammation by promoting alveolar macrophages’ polarization towards M2 ( Yuan et al, 2022 ). Furthermore, many studies have suggested that metformin exerts vascular protective effect on ECs.…”

Section: Discussionmentioning

confidence: 99%

Metformin alleviates lung-endothelial hyperpermeability by regulating cofilin-1/PP2AC pathway

et al. 2023

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Background: Microvascular endothelial hyperpermeability is an earliest pathological hallmark in Acute Lung Injury (ALI), which progressively leads to Acute Respiratory Distress Syndrome (ARDS). Recently, vascular protective and anti-inflammatory effect of metformin, irrespective of glycemic control, has garnered significant interest. However, the underlying molecular mechanism(s) of metformin’s barrier protective benefits in lung-endothelial cells (ECs) has not been clearly elucidated. Many vascular permeability-increasing agents weakened adherens junctions (AJ) integrity by inducing the reorganization of the actin cytoskeleton and stress fibers formation. Here, we hypothesized that metformin abrogated endothelial hyperpermeability and strengthen AJ integrity via inhibiting stress fibers formation through cofilin-1-PP2AC pathway.Methods: We pretreated human lung microvascular ECs (human-lung-ECs) with metformin and then challenged with thrombin. To investigate the vascular protective effects of metformin, we studied changes in ECs barrier function using electric cell-substrate impedance sensing, levels of actin stress fibers formation and inflammatory cytokines IL-1β and IL-6 expression. To explore the downstream mechanism, we studied the Ser3-phosphorylation-cofilin-1 levels in scramble and PP2AC-siRNA depleted ECs in response to thrombin with and without metformin pretreatment.Results: In-vitro analyses showed that metformin pretreatment attenuated thrombin-induced hyperpermeability, stress fibers formation, and the levels of inflammatory cytokines IL-6 and IL-β in human-lung-ECs. We found that metformin mitigated Ser3-phosphorylation mediated inhibition of cofilin-1 in response to thrombin. Furthermore, genetic deletion of PP2AC subunit significantly inhibited metformin efficacy to mitigate thrombin-induced Ser3-phosphorylation cofilin-1, AJ disruption and stress fibers formation. We further demonstrated that metformin increases PP2AC activity by upregulating PP2AC-Leu309 methylation in human-lung-ECs. We also found that the ectopic expression of PP2AC dampened thrombin-induced Ser3-phosphorylation-mediated inhibition of cofilin-1, stress fibers formation and endothelial hyperpermeability.Conclusion: Together, these data reveal the unprecedented endothelial cofilin-1/PP2AC signaling axis downstream of metformin in protecting against lung vascular endothelial injury and inflammation. Therefore, pharmacologically enhancing endothelial PP2AC activity may lead to the development of novel therapeutic approaches for prevention of deleterious effects of ALI on vascular ECs.

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“…Metformin is a commonly used medication for diabetes. Metformin treatment has been shown to increase M2 macrophages and decrease M1 macrophages [120][121][122][123][124][125], likely through NLRP3 inflammasome Macrophages as a Target for Treating Diabetic Foot Ulcers DOI: http://dx.doi.org/10.5772/intechopen.106613 suppression, which was discussed above [123]. Melatonin is a medication not for diabetes.…”

Section: Strategies To Improve Diabetic Wound Healing Through Manipul...mentioning

confidence: 99%

Macrophages as a Target for Treating Diabetic Foot Ulcers

Zhu¹,

Xiao²,

Jiang³

et al. 2023

Diabetic Foot - Recent Advances

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In all stages of wound healing, macrophages play a pivotal role by coordinating the repair steps in a timely and accurate fashion. The successful completion of wound healing requires proper spatiotemporal presence and function of macrophages. Diabetes significantly alters the proliferation, polarization and functionality of macrophages, leading to a suboptimal but prolonged pro-inflammatory M1-like phenotype in wound macrophages and a failure of their late transition to a reparative M2-like phenotype. This defect in macrophage phenotype and the proper transition results in delayed or even failure of wound healing. Specifically in the diabetic foot ulcer (DFUs), this macrophage dysfunction results in chronic infection and potentially amputation. The abnormal macrophage phenotype in diabetes is not fully understood but is believed to mainly result from epigenetic changes in macrophages and altered interactions between macrophages and other cell types, such as fibroblasts, endothelial cells, neutrophils and T-cells. Recent research on DFUs has focused on developing strategies to improve diabetic wound repair through modulation of macrophage polarization. Treatment of DFUs will greatly benefit from a multi-modal therapy that includes controlling high blood glucose, topical support, prevention of secondary infection, resolution of sustained inflammation and application of cellular therapies targeting macrophages.

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Metformin Regulates Alveolar Macrophage Polarization to Protect Against Acute Lung Injury in Rats Caused by Paraquat Poisoning

Cited by 4 publications

References 33 publications

Effects of metformin on acute respiratory distress syndrome in preclinical studies: a systematic review and meta-analysis

Effects of metformin on acute respiratory distress syndrome in preclinical studies: a systematic review and meta-analysis

Metformin alleviates lung-endothelial hyperpermeability by regulating cofilin-1/PP2AC pathway

Macrophages as a Target for Treating Diabetic Foot Ulcers

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