Lipopolysaccharide promotes lung fibroblast proliferation through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway

Xie, Tingting; Xu, Qiaoyi; Wan, Hanxi; Xing, Shunpeng; Shang, Chao; Gao, Yuan; He, Zhengyu

doi:10.1038/s41374-018-0160-2

Cited by 31 publications

(24 citation statements)

References 25 publications

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“…Moreover, overexpression of PI3K reversed the protection of miR-146b-3p overexpression on lung injury. Our results were also consistent with previous reports on ARDS in septic mice (Afshari et al 2010;Mittal and Sanyal 2012;Ding et al 2017;Xie et al 2019;Pham and Rubenfeld 2017).…”

Section: Discussionsupporting

confidence: 94%

Up-regulation of miR-146b-3p protects septic mice with acute respiratory distress syndrome by inhibiting PI3K/AKT signaling pathway

Liu

Zhu

Jin

et al. 2020

J Bioenerg Biomembr

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This study aimed to explore the role of miR-146b-3p in acute respiratory distress syndrome in septic mice. Ten mice were randomly selected as normal group (n = 10, without any treatment) and 60 septic mice with acute respiratory distress syndrome were divided into model group (n = 10, without any treatment), negative control (NC) mimic group (n = 10, injected with NC mimic), miR-146b-3p mimic group (n = 10, injected with miR-146b-3p mimic), si-NC group (n = 10, injected with PI3Kγ siRNA NC), si-PI3Kγ group (n = 10, injected with PI3Kγ silencing plasmid), and miR-146b-3p mimic + oe-PI3Kγ group (n = 10, injected with miR-146b-3p mimic + PI3Kγ overexpression plasmid). We found that miR-146b-3p negatively regulated PI3Kγ. Compared with normal group, model mice had decreased expression of miR-146b-3p, increased expressions of PI3Kγ, p-AKT, ASC, NLRP3 and Caspase-1 proteins, higher W/D ratio, and more serum IL-1β and IL-18 content (all P < 0.05). All indicators in miR-146b-3p mimic group and si-PI3Kγ group were significantly improved as compared to model group (all P < 0.05). Over-expression of PI3Kγ could weaken the treatment effect of miR-146b-3p mimic in model mice. Therefore, upregulation of miR-146b-3p can inhibit PI3K/AKT signaling pathway to improve acute respiratory distress syndrome in septic mice.

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Section: Discussionsupporting

confidence: 94%

Up-regulation of miR-146b-3p protects septic mice with acute respiratory distress syndrome by inhibiting PI3K/AKT signaling pathway

Liu

Zhu

Jin

et al. 2020

J Bioenerg Biomembr

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“…To further explore the upstream regulatory mechanism of PI3K/AKT signaling pathway, we verified the target relationship between PI3Kγ and miR-146b-3p through bioinformatics prediction website and confirmed through dual-luciferase reporter assay that miR-146b-3p negatively regulated PI3Kγ. Model levels, and improving tissue inflammation, which was consistent with previous reports on ARDS in septic mice [30][31][32][33][34].…”

Section: Discussionsupporting

confidence: 92%

miR-146b-3p regulates PI3K/AKT signaling pathway in septic mice with acute respiratory distress syndrome

Liu¹,

Zhu²,

Jin³

et al. 2020

Preprint

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Background: This study aimed to explore the effect of miR-146b-3p on acute respiratory distress syndrome in septic mice by regulating PI3K/AKT signaling pathway. Methods: Seventy C57BL/6 mice were divided into normal group ( n = 10) and modeling group ( n = 60, mice for constructing septic mice models with acute respiratory distress syndrome). Model mice were subdivided into model group (without any treatment), negative control (NC) mimic group (injection with miRNA NC), miR-146b-3p mimic group (injection with miR-146b-3p mimic), si-NC group (injection with PI3Kγ siRNA NC), si-PI3Kγ group (injection with PI3Kγ interference sequence), and miR-146b-3p mimic + oe-PI3Kγ group (injection with miR-146b-3p mimic + PI3Kγ overexpression plasmid). Dual-luciferase reporter assay was conducted to determine the target relationship between miR-146b-3p and PI3Kγ. Wet weight/dry weight (W/D) ratio of the left lung was measured. Hematoxylin and eosin stain was used to detect the pathological change of mouse lung. ELISA was employed to measure serum interleukin (IL) -1β and IL-18 levels. miR-146b-3p and PI3Kγ expressions were detected by qRT-PCR. PI3Kγ, AKT, NLRP3, apoptosis-associated speck-like protein caspase recruitment domain (ASC) and Caspase-1 protein expressions were detected by Western blotting. Results: miR-146b-3p negatively regulated PI3Kγ. The lung tissues in other groups compared with normal group had down-regulated miR-146b-3p, up-regulated PI3Kγ, p-AKT, ASC, NLRP3 and Caspase-1 proteins, higher W/D ratio, and more serum IL-1β and IL-18 (all P < 0.05). All indicators in miR-146b-3p mimic group and si-PI3Kγ group were significantly improved as compared to model group (all P < 0.05). Up-regulated PI3Kγ, p-AKT, ASC, NLRP3 and Caspase-1 proteins and higher W/D ratio and IL-1β and IL-18 levels in serum existed in miR-146b-3p mimic + oe-PI3Kγ group compared with miR-146b-3p mimic group (all P < 0.05). Conclusions: Up-regulation of miR-146b-3p can restrain PI3K/AKT signaling pathway, thereby improving acute respiratory distress syndrome in septic mice.

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“…Studies have shown that the PI3K-Akt pathway controlling mTOR expression negatively regulates autophagy in cells [26,27]. Our previous study demonstrated that LPS activates the PI3K-Akt-mTOR pathway and inhibits autophagy in lung fibroblasts [9]. However, the mechanism by which LPS induces PI3K-Akt-mTOR pathway activation remains unclear.…”

Section: Discussionmentioning

confidence: 97%

“…Previous studies have shown that autophagy inhibition in lung tissues is closely associated with pulmonary fibrosis [7,8]. In addition, our recent study revealed that LPS could inhibit lung fibroblast autophagy by activating the phosphatidylinositol-3-kinaseprotein kinase B-mammalian target of rapamycin (PI3K-Akt-mTOR) pathway [9]. However, the mechanism underlining LPS-induced PI3K-Akt-mTOR pathway activation and lung fibroblast autophagy inhibition remains largely unknown.…”

Section: Introductionmentioning

confidence: 97%

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

Wan

Xie

et al. 2019

Laboratory Investigation

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ARTICLEThy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis Abstract Lipopolysaccharide (LPS)-induced autophagy inhibition in lung fibroblasts is closely associated with the activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR) pathway. However, the underlying mechanism remains unknown. In this study, we demonstrated that LPS activated the PI3K-Akt-mTOR pathway and inhibited lung fibroblast autophagy by depleting thymocyte differentiation antigen-1 (Thy-1) and upregulating integrin β3 (Itgb3). Challenge of the human lung fibroblast MRC-5 cell line with LPS resulted in significant upregulation of integrin β3, activation of the PI3K-Akt-mTOR pathway and inhibition of autophagy, which could be abolished by integrin β3 silencing by specific shRNA or treatment with the integrin β3 inhibitor cilengitide. Meanwhile, LPS could inhibit Thy-1 expression accompanied with PI3K-Akt-mTOR pathway activation and lung fibroblast autophagy inhibition; these effects could be prevented by Thy-1 overexpression. Meanwhile, Thy-1 downregulation with Thy-1 shRNA could mimic the effects of LPS, inducing the activation of PI3K-Akt-mTOR pathway and inhibiting lung fibroblast autophagy. Furthermore, protein immunoprecipitation analysis demonstrated that LPS reduced the binding of Thy-1 to integrin β3. Thy-1 downregulation, integrin β3 upregulation and autophagy inhibition were also detected in a mouse model of LPS-induced pulmonary fibrosis, which could be prohibited by intratracheal injection of Thy-1 overexpressing adeno-associated virus (AAV) or intraperitoneal injection of the integrin β3 inhibitor cilengitide. In conclusion, this study demonstrated that Thy-1 depletion and integrin β3 upregulation are involved in LPS-induced pulmonary fibrosis, and may serve as potential therapeutic targets for pulmonary fibrosis.

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Lipopolysaccharide promotes lung fibroblast proliferation through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway

Cited by 31 publications

References 25 publications

Up-regulation of miR-146b-3p protects septic mice with acute respiratory distress syndrome by inhibiting PI3K/AKT signaling pathway

Up-regulation of miR-146b-3p protects septic mice with acute respiratory distress syndrome by inhibiting PI3K/AKT signaling pathway

miR-146b-3p regulates PI3K/AKT signaling pathway in septic mice with acute respiratory distress syndrome

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

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