Department of Anesthesiology, School and Hospital of Stomatological, China Medical University, Liaoning Provincial Key Laboratory of Ora Disease, No. 117 Nanjing North Street, Heping District, Shenyang, 110002, China.
J Anesth. 2021 Jun;35(3):394-404. doi: 10.1007/s00540-021-02909-9. Epub 2021 Apr 5.
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.
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.
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.
These data suggest that DEX ameliorates LPS-induced acute lung injury partly through the PI3K/Akt/FoxO1 signaling pathway.
右美托咪定（DEX）与炎症、氧化应激和细胞凋亡有关，但它对脂多糖（LPS）诱导的肺损伤的影响尚不确定。本研究通过检测磷酸肌醇 3-激酶（PI3K）抑制剂 LY294002 和 BEZ235 的作用，探讨了 DEX 对 LPS 诱导的肺损伤的影响，并研究了可能的分子机制。
70 只 C57BL/6 小鼠随机分为对照组、LPS 组、LPS+DEX 组、LPS+LY294002 组、LPS+BEZ235 组、LPS+DEX+LY294002 组和 LPS+DEX+BEZ235 组。LPS 处理后 48 小时收集肺组织样本。
DEX 显著抑制 LPS 诱导的肺重/体重比和肺湿/干重比增加，减少炎症细胞浸润，并减少白细胞介素-1β（IL-1β）、IL-6 和肿瘤坏死因子-α（TNF-α）等促炎因子在肺中的产生。DEX 还明显减弱 MDA5 和肌醇依赖性酶 a（IRE-a）的增加，减弱超氧化物歧化酶 1（SOD-1）的减少，逆转 B 细胞淋巴瘤-2（Bcl-2）的低表达，以及 Bax 和 Caspase-3 的高表达。DEX 还降低了磷酸化 PI3K 和磷酸化 Akt 的表达，增加了叉头框 O 转录因子 1（FoxO1）的表达。更有趣的是，LY294002 或 BEZ235 预处理显著消除了 DEX 对 LPS 诱导的肺炎症、氧化应激和细胞凋亡的抑制作用。
这些数据表明，DEX 通过 PI3K/Akt/FoxO1 信号通路改善 LPS 诱导的急性肺损伤。
