巴瑞替尼对脂多糖诱导小鼠急性肺损伤的治疗作用研究OACSTPCD
Effects of baricitinib in treatment of lipopolysaccharide-induced acute lung injury in mice
背景 急性肺损伤(acute lung injury,ALI)是一类危及生命的呼吸系统疾病,病死率高,目前缺乏有效的靶向干预措施.目的 探究巴瑞替尼(baricitinib)对脂多糖(lipopolysaccharide,LPS)诱导的小鼠急性肺损伤的治疗作用.方法 将36只周龄 8 周的雄性C57BL/6J小鼠随机分为对照组、ALI组和治疗组(ALI+baricitinib),每组 12只.治疗组给予巴瑞替尼30 mg/kg灌胃 1次,1 h后ALI组和治疗组以单次气管滴注注射LPS(10 mg/kg,溶于 50 μL 0.9%氯化钠注射液)的方式构建小鼠急性肺损伤模型,同时对照组小鼠给予气管滴注等剂量0.9%氯化钠注射液.气管滴注脂多糖或0.9%氯化钠注射液24h后,取小鼠肺组织和肺泡灌洗液(bronchoalveolar lavage fluid,BALF).观察小鼠一般情况及肺大体情况;HE染色观察各组小鼠肺组织损伤状况;检测各组小鼠肺活量(vital capacity,VC)、深吸气量(inspiratory capacity,IC)、准静态肺顺应性(chord compliance,Cchord)和动态肺顺应性(dyanamic compliance,Cdyn)等肺功能指标;记录各组小鼠肺组织湿干质量比值(wet/dry mass,W/D);BCA蛋白定量法检测BALF中的总蛋白水平;分析BALF中的细胞总数及中性粒细胞数量变化;ELISA实验分析BALF中白细胞介素 6(interleukin-6,IL-6)、IL-1β及肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)的水平;RT-qPCR技术检测小鼠肺组织中IL-6、IL-1β及TNF-α的转录水平.结果 与对照组相比,ALI组小鼠肺组织出现肺损伤,各项肺功能指标显著降低(P<0.01),肺组织W/D升高(P<0.01),BALF中的蛋白浓度、细胞数量及炎症因子水平升高(P<0.01),肺组织中炎症因子的表达水平升高(P<0.01);与ALI组相比,治疗组小鼠肺组织损伤情况显著改善,肺功能指标中Cdyn升高(P<0.05),肺组织W/D降低(P<0.001),BALF中的蛋白浓度、细胞数量及炎症因子水平降低(P<0.01),肺组织中炎症因子的表达水平降低(P<0.01).结论 巴瑞替尼预处理可一定程度减轻脂多糖诱导的小鼠急性肺损伤.
Background Acute lung injury(ALI)is a life-threatening respiratory disease with a high mortality rate,and there is a lack of effective targeted interventions.Objective To explore the therapeutic effect of baricitinib on lipopolysaccharide(LPS)-induced acute lung injury in mice.Methods A total of 36 male C57BL/6J mice aged 8 weeks were randomly divided into the control group(n=12),ALI group(n=12),and treatment group(ALI+baricitinib,n=12).The treatment group was given baricitinib 30 mg/kg intragastric administration once;one hour later,ALI group and treatment group were given a single tracheal infusion of LPS(10 mg/kg,dissolved in 50uL normal saline)to establish a mouse model of acute lung injury,while the control group was given tracheal infusion of equal dose of normal saline.After 24 h of endotracheal infusion of lipopolysaccharide or normal saline,the lung tissue and bronchoalveolar lavage fluid(BALF)were collected.The lung tissue injury was observed by hematoxylin-eosin(HE)staining.Vital capacity(VC),inspiratory capacity(IC),chord compliance(Cchord),and dyanamic compliance(Cdyn)were detected.The wet-dry mass(W/D)ratio of lung tissue was recorded.The total protein level in BALF was detected by the BCA protein quantitative method,and the total number of cells and neutrophils in BALF were analyzed.The levels of interleukin-6(IL-6),interleukin-1β(IL-1β)and tumor necrosis factor-α(TNF-α)in BALF were analyzed by ELISA.RT-qPCR was used to detect the transcription levels of IL-6,IL-1β and TNF-α in mouse lung tissue.Results Compared with the control group,the lung tissue of the ALI group showed obvious lung injury,the lung function indexes decreased significantly(P<0.001),while the lung tissue W/D was significantly increased(P<0.001),and the protein concentration,cell number,and inflammatory factor levels in BALF were also significantly increased(P<0.01).The expression level of inflammatory factors in lung tissue was significantly increased(P<0.01).Compared with ALI group,the lung tissue injury of mice in the treatment group was significantly improved,the lung function index of Cdyn was increased(P<0.05),the lung tissue W/D was decreased(P<0.001),the protein concentration,cell number and inflammatory factors in BALF were decreased(P<0.01).The expression level of inflammatory factors in lung tissue was decreased(P<0.01).Conclusion Baritinib pretreatment can alleviate acute lung injury induced by lipopolysaccharide to some extent.
孙亚楠;周禹;刘雯丽;张天泰;孙岚;梁志欣
解放军总医院第一医学中心呼吸与危重症医学科,北京 100853中国医学科学院药物研究所,北京 100050
临床医学
巴瑞替尼Jak/Stat信号通路脂多糖急性肺损伤小鼠肺功能
baricitinibJak/Stat signal pathwaylipopolysaccharideacute lung injurymouse lung function
《解放军医学院学报》 2024 (006)
638-643 / 6
国家重点研发计划课题(2022YFA1104704)
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