Wang Yu-Ming, Qi Xing, Gong Fang-Chen, Chen Ying, Yang Zhi-Tao, Mao En-Qiang, Chen Er-Zhen
Department of Emergency in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Department of Emergency in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
Int Immunopharmacol. 2020 Jun;83:106438. doi: 10.1016/j.intimp.2020.106438. Epub 2020 Apr 1.
We aimed to investigate whether inhibition of MUC1 would aggravate sepsis-induced ALI, and explore the predictive value of plasma MUC1 for sepsis patients with or without ARDS.
MUC1 siRNA pre-treatment was used to knockdown MUC1 expression in vitro. GO203 was used to inhibit the homodimerization of MUC1-C in vivo. Expression levels of MUC1, TLR 4 and HIF-1α were detected by Western blot. In addition, plasma MUC1 levels of enrolled patients were detected by ELISA on the day of admission and on the 3rd day. ROC curve was used to determine the predictive value of MUC1 in sepsis patients with ARDS.
Our results showed that inhibition of MUC1 could aggravate sepsis-induced acute lung injury and increase the expression of inflammatory cytokines in sera and BALF of sepsis mice. At the same time, we confirmed that inhibition of MUC1 could significantly decrease HIF-1α expression and thereby activate the expression level of TLR4. HIF-1α was a negative regulator of TLR-4. In addition, plasma MUC1 levels of sepsis patients with ARDS were significantly higher than those without ARDS and healthy adults. ROC curve showed that predictive value of plasma MUC1 on sepsis with ARDS on the 3rd day of enrollment was higher than the day of enrollment.
MUC1 could inhibit the expression of TLR-4 by stabilizing HIF-1α, thereby alleviate sepsis-induced lung injury and protect organ function. At the same time, elevated MUC1 levels in plasma had a good predictive valud on whether patients with sepsis would develop ARDS.
我们旨在研究抑制MUC1是否会加重脓毒症诱导的急性肺损伤，并探讨血浆MUC1对有或无急性呼吸窘迫综合征（ARDS）的脓毒症患者的预测价值。
在体外使用MUC1小干扰RNA（siRNA）预处理来降低MUC1表达。在体内使用GO203抑制MUC1-C的同源二聚化。通过蛋白质免疫印迹法检测MUC1、Toll样受体4（TLR 4）和缺氧诱导因子-1α（HIF-1α）的表达水平。此外，在入院当天和第3天通过酶联免疫吸附测定法（ELISA）检测入组患者的血浆MUC1水平。使用受试者工作特征曲线（ROC曲线）来确定MUC1在ARDS脓毒症患者中的预测价值。
我们的结果表明，抑制MUC1会加重脓毒症诱导的急性肺损伤，并增加脓毒症小鼠血清和支气管肺泡灌洗液（BALF）中炎性细胞因子的表达。同时，我们证实抑制MUC1可显著降低HIF-1α表达，从而激活TLR4的表达水平。HIF-1α是TLR-4的负调节因子。此外，伴有ARDS的脓毒症患者的血浆MUC1水平显著高于无ARDS的脓毒症患者和健康成年人。ROC曲线显示，入组第3天血浆MUC1对伴有ARDS的脓毒症的预测价值高于入院当天。
MUC1可通过稳定HIF-1α来抑制TLR-4的表达，从而减轻脓毒症诱导的肺损伤并保护器官功能。同时，血浆中MUC1水平升高对脓毒症患者是否会发生ARDS具有良好的预测价值。
