摘要
目的探讨杜鹃素(Farrerol)对脓毒症诱导的小鼠急性肺损伤(ALI)的治疗作用及其机制。方法盲肠结扎和穿刺(CLP)操作用于建立脓毒症诱导的C57BL/6J小鼠急性肺损伤模型,将小鼠随机分为对照组、CLP组、CLP+Farrerol 40 mg/kg组、CLP+Farrerol 40 mg/kg+30 mg/kg ML385(Nrf2特异性抑制剂)组(n=6)。CLP操作24 h后,收集肺组织和支气管肺泡液(BALF),苏木精-伊红(HE)染色用于分析肺组织病理学变化;比色法检测髓过氧化物酶(MPO)、铁水平、丙二醛(MDA)和谷胱甘肽(GSH);ELISA法检测炎症因子水平;Western blot用于检测紧密连接因子、铁死亡和Nrf2/HO-1通路相关蛋白的表达。结果与对照组比较,CLP组小鼠存活率明显降低,且肺组织出现明显病理损伤(均P<0.05)。与CLP组相比,Farrerol 10、20、40 mg组肺组织病理损伤明显改善,肺组织评分显著降低(均P<0.05)。与对照组比较,CLP组肺湿/干比值、BALF总蛋白浓度、MPO活性显著升高,ZO-1、occludin、claudin-1蛋白表达显著增多,肿瘤坏死因子α(TNF-α)、IL-1β、IL-6水平显著增加,铁含量积累、MDA含量显著减少,GSH活性、SLC7A11和GPX4蛋白表达显著升高,Nrf2和HO-1蛋白表达显著升高(均P<0.05)。与CLP组相比,CLP+Farrerol组改善脓毒症小鼠肺泡上皮屏障功能,减少炎症因子释放并激活Nrf2/HO-1通路,抑制肺组织铁死亡(均P<0.05)。与CLP+Farrerol组相比,CLP+Farrerol+ML385组消除了Farrerol对ALI的保护作用(P<0.05)。结论杜鹃素通过激活Nrf2/HO-1通路抑制铁死亡,改善脓毒症诱导的小鼠急性肺损伤,为脓毒症的治疗提供了新的基础。
Objective To explore the therapeutic effect and mechanism of Farrerol on sepsis induced acute lung injury(ALI)in mice.Methods The cecal ligation and puncture(CLP)procedure was used to establish a sepsis-induced ALI model in C57BL/6J mice.The mice were randomly divided into groups:control group,CLP group,CLP+Farrerol 40 mg/kg group,CLP+Farrerol 40 mg/kg+30 mg/kg ML385(Nrf2 specific inhibitor)group.After 24 h of CLP operation,collected lung tissue and bronchoalveolar fluid(BALF),and hematoxylin eosin(HE)staining was used to analyze pathological changes in lung tissues.The colorimetry was used to detected myeloperoxidase(MPO),iron levels,malondialdehyde(MDA),and glutathione(GSH).ELISA method was used to detect the level of inflammatory cytokines.Western blot was used to detect the expression of tight junction factor,ferroptosis,and Nrf2/HO-1 pathway related proteins.Results Compared with the control group,the survival rate of CLP group mice was significantly reduced,and significant pathological damage was observed in lung tissues.Compared with CLP group,the pathological damage of lung tissue was significantly improved,and the lung tissue score was significantly decreased in the farrerol 10,20 and 40 mg/kg groups,the CLP group showed a significant increase in lung wet/dry ratio,BALF total protein concentration,MPO activity,and the expression of ZO-1,occludin,and claudin-1 proteins,as well as the level of TNF-α、IL-1β、IL-6 significantly increased.Compared with the control group,the accumulation of iron content and MDA content in the CLP group were significantly reduced,while GSH activity,SLC7A11 and GPX4 protein expression were significantly increased,and Nrf2 and HO-1 protein expression were significantly increased.Compared with the CLP group,Farrerol improved the alveolar epithelial barrier function in septic mice,reduced inflammation,and inhibited ferroptosis in lung tissue.Compared with the CLP+Farrerol 40 mg/kg group,ML385 eliminated the protective effect of Farrerol on ALI.Conclusion Farrerol inhibites ferroptosis and inflammatory response by activating the Nrf2/HO-1 pathway,improves sepsis induced acute lung injury in mice,which provides a new basis for the treatment of sepsis.
作者
张志炜
贾旭林
ZHANG Zhiwei;JIA Xulin(Department of Emergency,Shanxi Maternal and Child Health Hospital,Shanxi Children's Hospital,Taiyuan 030013,China)
出处
《西部医学》
2025年第6期827-832,837,共7页
Medical Journal of West China
基金
山西省科技厅科研基金项目(201901D111497)。
