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牛磺酸通过抑制 p38/MAPK 信号通路对脓毒症诱导的肺损伤的保护作用。

Protective effect of taurine on sepsis‑induced lung injury via inhibiting the p38/MAPK signaling pathway.

机构信息

Department of Critical Care Medicine, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China.

Department of Emergency Medicine, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China.

出版信息

Mol Med Rep. 2021 Sep;24(3). doi: 10.3892/mmr.2021.12292. Epub 2021 Jul 19.

Abstract

Sepsis, a leading cause of acute lung injury (ALI), is characterized by an overwhelming systemic inflammatory response and widespread organ injury, particularly in the lungs. Taurine, an intracellular free amino acid, has been used for the treatment of various diseases, including lung injury; however, the underlying mechanisms are unclear. The present study aimed to investigate the protective effect of taurine on septic ALI and the underlying mechanism. A septic ALI model was established by performing cecal ligation and puncture (CLP) surgery on Sprague Dawley rats. Following successful model establishment, rats were treated with taurine. The results of hematoxylin and eosin, respiratory function detection, malondialdehyde level and superoxide dismutase activity determination and ELSIA demonstrated that taurine significantly alleviated lung injury, restored respiratory function, reduced oxidation and decreased the concentrations of inflammatory factors in CLP‑induced septic ALI model rats. In addition, compared with that in the ALI group, western blotting results indicated that taurine ameliorated lung epithelial injury by significantly increasing the expression levels of lung epithelial markers, E‑cadherin and occludin. The western blotting results demonstrated that, compared with the control group, the p38/MAPK and NF‑κB signaling pathways were significantly activated in CLP‑induced septic ALI model rats, but taurine significantly suppressed ALI‑mediated signaling pathway activation. To investigate the mechanism underlying taurine in the treatment of septic ALI, CLP‑induced septic ALI model rats were treated with an antagonist of the p38/MAPK signaling pathway (SB203580). The effects of SB203580 on CLP‑induced septic ALI model rats were similar to those of taurine. SB203580 significantly attenuated sepsis‑induced lung injury and increases in IL‑1β and TNF‑α concentrations in the lung tissue. In addition, SB203580 promoted restoration of the injured lung tissue and respiratory function in CLP‑induced septic ALI model rats. The western blotting results indicated that SB203580 significantly decreased the ratios of phosphorylated (p)‑p38/p38 and p‑p65/065, and increased the protein expression levels of E‑cadherin and occludin compared with those in the ALI group. In summary, the present study demonstrated that taurine alleviated sepsis‑induced lung injury, which was associated with suppression of the inflammatory response and oxidative stress via inhibiting the p38/MAPK signaling pathway. Therefore, the p38/MAPK signaling pathway may serve as a potential therapeutic target for the treatment of sepsis‑induced ALI.

摘要

脓毒症是急性肺损伤(ALI)的主要病因,其特征是全身性炎症反应和广泛的器官损伤,尤其是在肺部。牛磺酸是一种细胞内游离氨基酸,已被用于治疗各种疾病,包括肺损伤;然而,其潜在机制尚不清楚。本研究旨在探讨牛磺酸对脓毒症性 ALI 的保护作用及其潜在机制。通过对 Sprague Dawley 大鼠进行盲肠结扎和穿刺(CLP)手术建立脓毒症性 ALI 模型。成功建立模型后,大鼠用牛磺酸进行治疗。苏木精-伊红染色、呼吸功能检测、丙二醛水平和超氧化物歧化酶活性测定以及 ELISA 结果表明,牛磺酸可显著减轻肺损伤,恢复呼吸功能,降低氧化应激并降低 CLP 诱导的脓毒症性 ALI 模型大鼠中炎症因子的浓度。此外,与 ALI 组相比,Western blot 结果表明,牛磺酸通过显著增加肺上皮标志物 E-钙黏蛋白和闭合蛋白的表达水平来改善肺上皮损伤。Western blot 结果表明,与对照组相比,CLP 诱导的脓毒症性 ALI 模型大鼠中 p38/MAPK 和 NF-κB 信号通路明显被激活,但牛磺酸可显著抑制 ALI 介导的信号通路激活。为了研究牛磺酸治疗脓毒症性 ALI 的机制,用 p38/MAPK 信号通路的拮抗剂(SB203580)处理 CLP 诱导的脓毒症性 ALI 模型大鼠。SB203580 对 CLP 诱导的脓毒症性 ALI 模型大鼠的影响与牛磺酸相似。SB203580 可显著减轻脓毒症引起的肺损伤并降低肺组织中白细胞介素-1β和肿瘤坏死因子-α的浓度。此外,SB203580 促进了 CLP 诱导的脓毒症性 ALI 模型大鼠受损肺组织和呼吸功能的恢复。Western blot 结果表明,与 ALI 组相比,SB203580 显著降低了磷酸化(p)-p38/p38 和 p-p65/p65 的比值,并增加了 E-钙黏蛋白和闭合蛋白的蛋白表达水平。综上所述,本研究表明,牛磺酸通过抑制 p38/MAPK 信号通路减轻脓毒症引起的肺损伤,这与抑制炎症反应和氧化应激有关。因此,p38/MAPK 信号通路可能是治疗脓毒症性 ALI 的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/71ad/8299207/f57471c58679/mmr-24-03-12292-g00.jpg

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