Metformin attenuates lipopolysaccharide‐induced epithelial cell senescence by activating autophagy

Abstract

Acute lung injury (ALI) is a life‐threatening medical condition with higher mortality and morbidity in elderly patients. Recently, metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, has been shown to be an effective anti‐inflammatory agent in ALI. However, the mechanism of this regulation still remains poorly understood. In our study, we found that epithelial cell senescence was elevated after lipopolysaccharide (LPS) exposure in vivo and in vitro, accompanied by decreased expression of ATG5 and impaired autophagy activity. To further discover the molecular regulation mechanism between cellular senescence and autophagy in LPS‐treated MLE‐12 cells, we demonstrated that inhibition of ATG5 could decrease autophagy levels and promote the senescence of MLE‐12 cells. On the contrary, elevating the expression of ATG5 could effectively suppress LPS‐induced cellular senescence via enhancing autophagy activity. In addition, we demonstrated that metformin could protect MLE‐12 cells from LPS‐induced senescence via increasing the expression of ATG5 and augmenting autophagy activity. Our data implicate that activation of autophagy by metformin may provide a preventive and therapeutic strategy for ALI.

Sophoridine inhibits endotoxin-induced acute lung injury by enhancing autophagy of macrophage and reducing inflammation

“…Studies have shown that LPS can activate autophagosome formation in mice. These studies suggest that autophagy may be an adaptive response to LPS‐induced ALI, 33 which aligns with the results of our study. LPS can enhance autophagy and increase the expression of the autophagy‐related proteins, LC3II/I and Beclin1.…”

“…32 Studies have shown that LPS can activate autophagosome formation in mice. These studies suggest that autophagy may be an adaptive response to LPS-induced ALI, 33 Autophagy is closely related to inflammation. The process of autophagy involves many relevant proteins that can swallow and kill pathogens to protect cells from pathogens and inhibit the secretion of inflammasomes and inflammatory factors.…”

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

“…Rapamycin protects alveolar epithelial cells from apoptosis and attenuates silica-induced pulmonary fibrosis through the enhancement of autophagy in the mouse model ( Zhao et al, 2019 ). Emerging evidence indicated that autophagy plays an import role in the beneficial effects of metformin ( Bharath et al, 2020 ; Ren et al, 2020 ).Metformin attenuates lipopolysaccharide-induced epithelial cell senescence by activating autophagy ( Wang et al, 2021 ). Bharath et al (2020) showed that metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation.…”

Pulmonary endogenous progenitor stem cell subpopulation: Physiology, pathogenesis, and progress

“…Recently, several studies have focused on the contribution of senescent AT2 cells to the pathogenesis of lung diseases. A large number of senescent AT2 cells were found in COVID-19-induced acute lung injury (ALI), [104] ventilation, [105] influenza, [106] LPS, [107] and chronic lung diseases, such as lung fibrosis and COPD. [108 , 109] Senescent AT2 cells exhibited lower regenerative capacity, as demonstrated by their impaired regeneration-related signaling pathways, [108] decreased AT2 and AT1 cell markers, [110] minimal stemness markers, [111] and lower proliferation markers.…”