Metformin Attenuates Silica-Induced Pulmonary Fibrosis by Activating Autophagy via the AMPK-mTOR Signaling Pathway

Abstract

Long-term exposure to crystalline silica particles leads to silicosis characterized by persistent inflammation and progressive fibrosis in the lung. So far, there is no specific treatment to cure the disease other than supportive care. In this study, we examined the effects of metformin, a prescribed drug for type || diabetes on silicosis and explored the possible mechanisms in an established rat silicosis model in vivo, and an in vitro co-cultured model containing human macrophages cells (THP-1) and human bronchial epithelial cells (HBEC). Our results showed that metformin significantly alleviated the inflammation and fibrosis of lung tissues of rats exposed to silica particles. Metformin significantly reduced silica particle-induced inflammatory cytokines including transforming growth factor-β1 (TGF-β1), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in rat lung tissue and HBEC culture supernatant. The protein levels of Vimentin and α-smooth muscle actin (α-SMA) were significantly decreased by metfomin while expression level of E-cadherin (E-Cad) increased. Besides, metformin increased the expression levels of phosphorylated adenosine 5′-monophosphate (AMP)-activated protein kinase (p-AMPK), microtubule-associated protein (MAP) light chain 3B (LC3B) and Beclin1 proteins, and reduced levels of phosphorylated mammalian target of rapamycin (p-mTOR) and p62 proteins in vivo and in vitro. These results suggest that metformin could inhibit silica-induced pulmonary fibrosis by activating autophagy through the AMPK-mTOR pathway.

Metformin Alleviates Arthrofibrosis via Fibroblast Metabolic Reprogramming

“…The fibroblast-MΦ crosstalk underlying the therapeutic mechanism of metformin for arthrofibrosis is the novel finding of the present study. Previous similar studies largely focused on the cell-autonomous effect of metformin (Feng et al, 2017;Han et al, 2021;Kheirollahi et al, 2019;Li et al, 2021;McCloskey et al, 2020;Mummidi et al, 2016;Rangarajan et al, 2018;Sato et al, 2016;Tang et al, 2021), while the present study extended the mechanism of action of the drug by providing new evidence that metformin-induced fibroblast metabolic rewiring not only plays a cellautonomous role but also involves a noncell-autonomous role in the resolution of arthrofibrosis.…”

“…Several reports have shown that metformin can prevent and even reverse fibrotic processes in multiple organs, including the kidney, lung, and liver (Feng et al, 2017; Han et al, 2021; Kheirollahi et al, 2019; Li et al, 2021; McCloskey et al, 2020; Mummidi et al, 2016; Rangarajan et al, 2018; Sato et al, 2016; Tang et al, 2021). A recent study confirmed the positive effect of metformin in suppressing joint capsular fibrosis in a mouse model of knee contracture (Tokuda et al, 2021).…”

“…Metabolic modulator metformin has long been used as the first-line treatment for patients with type 2 diabetes mellitus because of high efficacy and safety profile of the drug. Several animal studies demonstrated that metformin can treat and prevent fibrosis in preclinical models of kidney, lung, heart, liver, and ovary (Feng, Wang, Zhang, & Xiao, 2017; Han et al, 2021; Kheirollahi et al, 2019; Li et al, 2021; McCloskey et al, 2020; Mummidi et al, 2016; Rangarajan et al, 2018; Sato et al, 2016; Tang, Xu, Ye, & Wang, 2021). Interestingly, the results of a recent metabolomic analysis showed that metformin treatment led to the suppression of the TCA cycle and elevation of lactate production in fibroblasts, implicating a metabolic shift from OXPHOS to aerobic glycolysis (Yan et al, 2019).…”

AMP-activated protein kinase-dependent nuclear localization of glyceraldehyde 3-phosphate dehydrogenase in senescent human diploid fibroblasts

“…As the PI3K/Akt pathway is involved in various biological processes, several on-target and off-target effects may be observed, which can limit the clinical development of AGING therapeutics. AMPK activators such as metformin, AICAR, poricoic acid A, and HL156A may function as potential therapeutic agents for both fibrosis and cancer in aging organs [61][62][63][64][65].…”

Interplay between exosomes and autophagy machinery in pain management: State of the art

“…In another study, it was indicated that the administration of metformin blunted fibrosis in a rat model induced by silica via the regulation of the AMPK-mTOR axis and induction of P62, Beclin-1, and LC3. Histological examination revealed the phenotype acquisition of pneumocytes within the lung parenchyma ( Li et al, 2021 ). Regarding the close relationship between mTOR and autophagy response, the application of pharmacological agents with the potential to regulate mTOR activity is an appropriate strategy for the regulation of NP.…”