Xin Yan, Zou Lili, Lang Shuhui
Department of Anesthesiology, Changchun Maternity Hospital, Changchun, Jilin 130042, P.R. China.
Department of Anesthesiology, General Hospital of Ning Xia Medical University, Yin Chuan, Ningxia 750004, P.R. China.
Exp Ther Med. 2021 Feb;21(2):141. doi: 10.3892/etm.2020.9573. Epub 2020 Dec 14.
The progression of acute lung injury (ALI) is attributable to inflammation and oxidative stress. The cell-permeable itaconate analog 4-octyl itaconate (4-OI) provides protection against inflammatory responses and oxidative stress. However, whether 4-OI can protect against ALI remains poorly understood. The aim of this study was to explore the protective effects of 4-OI against LPS-induced ALI and the underlying mechanisms using hematoxylin and eosin (H&E) to observe lung morphology, ELISA and reverse transcription-quantitative PCR to measure the levels of IL-1β, TNF-α and IL-6 and western blotting to examine the levels of PI3K, Akt and NF-κB. The present study demonstrates that intraperitoneal administration of 4-OI (25 mg/kg) 2 h before lipopolysaccharide (LPS; 5 mg/kg) intratracheal injection significantly alleviated the lung tissue injury induced by LPS, reducing the production of proinflammatory cytokines and reactive oxygen species (ROS) . Furthermore, 4-OI and the antioxidant N-acetyl-L-cysteine markedly suppressed PI3K and Akt phosphorylation in LPS-treated RAW264.7 macrophage cells . Further study demonstrated that a pharmacological inhibitor of the phosphoinositide 3-kinase (PI3K)-Akt pathway, LY294002, inhibited the expression of NF-κB p65 in the nuclear fraction and decreased the production of inflammatory cytokines. Collectively, the experimental results of the present study provide evidence that 4-OI significantly decreased LPS-induced lung inflammation by suppressing ROS-mediated PI3K/Akt/NF-κB signaling pathways. These results suggest that 4-OI could be a valuable therapeutic drug in the treatment of ALI.
急性肺损伤（ALI）的进展归因于炎症和氧化应激。细胞可渗透的衣康酸类似物4-辛基衣康酸（4-OI）可提供针对炎症反应和氧化应激的保护作用。然而，4-OI是否能预防ALI仍知之甚少。本研究的目的是利用苏木精和伊红（H&E）观察肺形态、酶联免疫吸附测定（ELISA）和逆转录定量聚合酶链反应（RT-qPCR）测量白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平以及蛋白质免疫印迹法检测磷脂酰肌醇-3激酶（PI3K）、蛋白激酶B（Akt）和核因子-κB（NF-κB）水平，探讨4-OI对脂多糖（LPS）诱导的ALI的保护作用及其潜在机制。本研究表明，在气管内注射LPS（5 mg/kg）前2小时腹腔注射4-OI（25 mg/kg）可显著减轻LPS诱导的肺组织损伤，减少促炎细胞因子和活性氧（ROS）的产生。此外，4-OI和抗氧化剂N-乙酰-L-半胱氨酸显著抑制LPS处理的RAW264.7巨噬细胞中PI3K和Akt的磷酸化。进一步研究表明，磷脂酰肌醇3激酶（PI3K）-Akt途径的药理学抑制剂LY294002抑制核组分中NF-κB p65的表达并减少炎性细胞因子的产生。总体而言，本研究的实验结果提供了证据，表明4-OI通过抑制ROS介导的PI3K/Akt/NF-κB信号通路显著降低LPS诱导的肺部炎症。这些结果表明，4-OI可能是治疗ALI的一种有价值的治疗药物。
