Dexmedetomidine ameliorates lipopolysaccharide-induced acute lung injury by inhibiting the PI3K/Akt/FoxO1 signaling pathway

Abstract

Purpose Dexmedetomidine (DEX) has been associated with inflammation, oxidative stress, and apoptosis, but its effects on lipopolysaccharide (LPS)-induced lung injury remain uncertain. The present study explored the effects of DEX on LPS-induced lung injury and studied the possible molecular mechanisms by testing the effects of the phosphoinositide-3 kinase (PI3K) inhibitor LY294002 and BEZ235. Methods Seventy C57BL/6 mice were randomly divided into the control, LPS, LPS + DEX, LPS + LY294002, LPS + BEZ235, LPS + DEX + LY294002, and LPS + DEX + BEZ235groups. Lung samples were collected 48 h after LPS treatment. Results DEX significantly inhibited LPS-induced increases in the lung weight/body weight ratio and lung wet/dry weight ratio, decreased inflammatory cell infiltration, and decreased the production of proinflammatory factors, such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α)in the lungs. DEX also markedly attenuated the increases in malondialdehyde 5 (MDA 5) and inositol-dependent enzyme a (IRE-a), attenuated the decrease in superoxide dismutase 1(SOD-1), reversed the low expression of B-cell lymphoma-2 (Bcl-2), and the high expressions of Bax and Caspase-3. DEX also decreased the expression of phosphorylated PI3K and phosphorylated Akt and increased the expression of phosphorylated forkhead box-O transcription factor 1 (FoxO1). More interestingly, LY294002 or BEZ235 pretreatment significantly abolished the inhibitory effects of DEX on LPS-induced lung inflammation, oxidative stress, and apoptosis. Conclusions These data suggest that DEX ameliorates LPS-induced acute lung injury partly through the PI3K/Akt/FoxO1 signaling pathway.

The potential mechanism of the Ruhao Dashi formula in treating acute pneumonia via network pharmacology and molecular docking

“…[64–66] In addition, LPS-induced acute lung injury, including lung inflammation, oxidative stress, and apoptosis, could be prevented by inhibiting the PI3K/Akt/FoxO1 signaling pathway. [67] These findings are consistent with our view that the PI3K/Akt signaling pathway is more important in the involvement of RDF against AP.…”

Dexmedetomidine Attenuates LPS-Stimulated Alveolar Type II Cells’ Injury through Upregulation of miR-140-3p and Partial Suppression of PD-L1 Involving Inactivating JNK-Bnip3 Pathway

“…It shows that the protective effect of DEX is closely related to the inhibition of inflammation. However, the mechanism by which DEX inhibits the inflammatory response has not been elucidated [16][17][18]. Studies have shown that DEX can regulate signaling pathways and genes associated with inflammation through interactions with several miRNAs [19].…”

Attenuation of the Severity of Acute Respiratory Distress Syndrome by Pomiferin through Blocking Inflammation and Oxidative Stress in an AKT/Foxo1 Pathway-Dependent Manner

“…Phosphorylated Foxo1 could be dephosphorylated to form Foxo1 once AKT is activated, leading to its nuclear translocation [ 45 ]. It has been demonstrated that both the activation of the AKT and the reduction of Foxo1 expression in the nucleus can give rise to lung pathological injury and ARDS [ 18 ]. Here, we found that LPS stimulation significantly promoted the phosphorylation of AKT and the dephosphorylation of Foxo1 in macrophages and lung tissues from mice with ARDS.…”

“…AKT/Foxo1 signaling pathway possesses multiple regulators as well as effectors including glucose, insulin, cytokines, and growth factors, displaying significant functions in cell survival, metabolism, inflammation, and oxidative stress [13][14][15][16]. Previous studies have demonstrated that changes in AKT activity levels in macrophages show significant impacts on polarization and activation of macrophages via regulating Foxo1 activity during ARDS [17,18]. Hence, AKT/Foxo1 pathway may be a critical signaling target in drug discovery and treatment of ARDS.…”