P2Y12 Receptor Antagonist Clopidogrel Attenuates Lung Inflammation Triggered by Silica Particles

Santana, Patrícia Teixeira; Luna-Gomes, Tatiana; Rangel-Ferreira, Marcos Vinicius; Tamura, Augusto Shuiti; Graça, Carolyne Lalucha Alves Lima Da; Machado, Mariana; Zin, Walter A.; Takiya, Christina Maeda; Faffe, Débora S.; Coutinho‐Silva, Robson

doi:10.3389/fphar.2020.00301

Cited by 10 publications

(8 citation statements)

References 54 publications

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“…It has been shown that macrophages, and inflammatory mediators, including IL-1β and TNF-α, could contribute to exacerbating lung fibrosis [ 39 ]. Besides, previous studies have suggested that AMPK could attenuate lipopolysaccharide (LPS)-stimulated pro-inflammatory factors and increase anti-inflammatory cytokine levels by reducing the transcription activity of nuclear factor-kappaB (NF-κB) in macrophages [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

Cheng

Wang

et al. 2021

J Transl Med

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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. Silicon dioxide (SiO2)-stimulated lung epithelial cells/macrophages and transforming growth factor-beta 1 (TGF-β1)-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 2–10 mM) 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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Section: Resultsmentioning

confidence: 99%

Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

Cheng

Wang

et al. 2021

J Transl Med

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“…Previous studies employing administration of higher doses of silica (20 mg/kg) demonstrated that histological alterations in the lung were accompanied by robust increases in pro-inflammatory cytokines [42,43]. Thus, we sought to determine whether the lower dose of silica employed here elicited a similar response.…”

Section: Discussionmentioning

confidence: 92%

Lung inflammation induced by silica particles triggers hippocampal inflammation, synapse damage and memory impairment in mice

Suman

Souza

Kincheski

et al. 2022

J Neuroinflammation

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Background Considerable evidence indicates that a signaling crosstalk between the brain and periphery plays important roles in neurological disorders, and that both acute and chronic peripheral inflammation can produce brain changes leading to cognitive impairments. Recent clinical and epidemiological studies have revealed an increased risk of cognitive impairment and dementia in individuals with impaired pulmonary function. However, the mechanistic underpinnings of this association remain unknown. Exposure to SiO2 (silica) particles triggers lung inflammation, including infiltration by peripheral immune cells and upregulation of pro-inflammatory cytokines. We here utilized a mouse model of lung silicosis to investigate the crosstalk between lung inflammation and memory. Methods Silicosis was induced by intratracheal administration of a single dose of 2.5 mg SiO2/kg in mice. Molecular and behavioral measurements were conducted 24 h and 15 days after silica administration. Lung and hippocampal inflammation were investigated by histological analysis and by determination of pro-inflammatory cytokines. Hippocampal synapse damage, amyloid-β (Aβ) peptide content and phosphorylation of Akt, a proxy of hippocampal insulin signaling, were investigated by Western blotting and ELISA. Memory was assessed using the open field and novel object recognition tests. Results Administration of silica induced alveolar collapse, lung infiltration by polymorphonuclear (PMN) cells, and increased lung pro-inflammatory cytokines. Lung inflammation was followed by upregulation of hippocampal pro-inflammatory cytokines, synapse damage, accumulation of the Aβ peptide, and memory impairment in mice. Conclusion The current study identified a crosstalk between lung and brain inflammatory responses leading to hippocampal synapse damage and memory impairment after exposure to a single low dose of silica in mice.

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“…It has been shown that macrophages, and in ammatory mediators, including IL-1β and TNF-α, could contribute to exacerbating lung brosis [34]. Thus, we detected the levels of in ammatory mediators in silica-stimulated macrophages by qRT-PCR analysis.…”

Section: Metformin Attenuates Sio2-induced Cell Cytotoxicitymentioning

confidence: 91%

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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P2Y12 Receptor Antagonist Clopidogrel Attenuates Lung Inflammation Triggered by Silica Particles

Cited by 10 publications

References 54 publications

Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

Metformin attenuates silica-induced pulmonary fibrosis via AMPK signaling

Lung inflammation induced by silica particles triggers hippocampal inflammation, synapse damage and memory impairment in mice

Metformin Attenuates Silica-induced Pulmonary Fibrosis via AMPK Signaling

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