ACT001通过STAT1/CIITA/MHC-Ⅱ通路发挥抗炎抗氧化活性治疗脓毒症引起的急性肺损伤  

ACT001 exerts anti-inflammatory and antioxidative activity to alleviate sepsis-induced acute lung injury through STAT1/CIITA/MHC-Ⅱpathway

作　　者：盛磊 周杰诗 韩旭 李伊楠 刘慧娟 孙涛[1] SHENG Lei;ZHOU Jie-shi;HAN Xu;LI Yi-nan;LIU Hui-juan;SUN Tao(College of Pharmacy,Nankai University,Tianjin 300350,China)

机构地区：[1]南开大学药学院,天津300350

出　　处：《中国药理学通报》2023年第12期2231-2239,共9页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金面上项目(No 82272934);国家级大学生创新创业训练计划(No 202210055112)。

摘　　要：目的评价含笑内酯衍生物ACT001对脓毒症进程中急性肺损伤的治疗作用并探究其药理机制。方法动物水平上,小鼠腹腔注射LPS建立急性肺损伤模型,腹腔注射ACT001进行治疗,从小鼠个体存活状况、肺部炎症损伤及水肿情况等方面评价ACT001的药效;细胞水平上,以LPS刺激RAW264.7细胞构建模型,通过检测炎症反应和氧化应激水平探究其药理机制,并通过蛋白质组学结果分析其相关分子机制。结果动物水平上,ACT001可改善急性肺损伤小鼠生存率、减轻肺部炎症、降低血清中炎症因子水平;细胞水平上,ACT001通过抑制MHC-Ⅱ相关通路,促进RAW264.7细胞向抗炎表型极化,抑制NO和相关炎症因子产生的同时提高SOD含量并清除ROS。结论ACT001通过抑制STAT1/CIITA/MHC-Ⅱ通路,发挥抗炎和抗氧化作用治疗急性肺损伤,有望开发为治疗脓毒症引起的急性肺损伤的新药。Aim This study aimed to assess the therapeutic potential of ACT001,a micheliolide derivative,in the treatment of acute lung injury(ALI)induced by sepsis and investigate its pharmacological mechanisms.Methods At the animal level,an ALI model was established in mice through intraperitoneal injection of lipopolysaccharide(LPS).Subsequently,ACT001 was administered to the ALI-afflicted mice.The therapeutic effects of ACT001 were assessed by evaluating factors such as individual survival rate,lung inflammation,and pulmonary edema.At the cellular level,RAW264.7 cells were stimulated with LPS to explore the pharmacological mechanism of ACT001.The study examined inflammatory response and oxidative stress levels,and proteomics analysis was conducted to investigate the underlying molecular mechanisms.Results At the animal level,ACT001 can improve the survival of mice with ALI,reduce lung inflammation,and reduce the levels of inflammatory cytokines in serum.At the cellular level,ACT001 promotes the polarization of RAW264.7 cells toward an anti-inflammatory phenotype by inhibiting MHC-II related pathways,inhibiting the production of NO and related inflammatory cytokines while increasing SOD content and scavenging ROS.Conclusions ACT001 exhibited the potential to alleviate ALI via its anti-inflammatory and antioxidative activity,mainly by inhibiting the STAT1/CIITA/MHC-Ⅱpathway.ACT001 holds promise as a novel therapeutic candidate for the treatment of ALI induced by sepsis.

关 键 词：ACT001 LPS 脓毒症 急性肺损伤 MHC-Ⅱ 抗原处理与呈递 

分 类 号：R-332[医药卫生] R284.1R322.35R364.5R631R563.8