NF-κB抑制剂对内毒素休克大鼠高迁移率族蛋白B1表达的影响

Effects of NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) on mRNA expression of high mobility group box-1 protein in organs of rats with endotoxic shock

目的 观察NF κB抑制剂———二硫氨基甲酸酞吡咯烷(PDTC)对内毒素休克大鼠高迁移率族蛋白B1(HMGB1)mRNA表达的影响。方法 采用内毒素休克模型 ,4 7只大鼠随机分为正常对照组 (n=8)、内毒素休克组(n =2 4 )和PDTC拮抗组 (n=15 ) ,留取肝、肺、肾组织检测HMGB1mRNA表达及相应器官功能指标的变化。结果 内毒素攻击可导致动物肝、肺、肾组织HMGB1mRNA表达广泛上调 ,分别于 2～6h显著增高 (P <0 0 5 ) ,12h呈现进一步升高趋势。PDTC处理后 12h肝、肺、肾组织HMGB1mRNA表达均显著下调 ,其中肾组织于 2～ 12h趋于伤前范围 ;同时 ,血清ALT、AST、BUN、Cr水平于 6h明显降低 (P <0 0 5 ) ,肺组织髓过氧化物酶活性各时相点均显著低于内毒素休克组 (P <0 0 5 )。结论 NF κB抑制剂能显著抑制内毒素休克动物组织HMGB1mRNA的表达 ;NF κB信号转导通路参与了内毒素介导HMGB1基因表达的调控过程 ,并与脓毒症时的多器官功能损害密切相关。

Objective To investigate the effect of nuclear factor-kappa B (NF-κB) signal transcription pathway inhibitor-pyrrolidine dithiocarbamate (PDTC) on mRNA expression of high mobility group box-1 protein (HMGB1) in organs of rats with endotoxic shock and its potential mechanism. Methods Forty-seven male Wistar rats were randomly divided into normal control group (n=8), endotoxic shock group (n=24), and PDTC treatment group (n=15). At serial time points, the animals in each group were sacrificed, and tissue samples from the liver, lungs and kidneys were harvested to determine HMGB1 mRNA expression and pulmonary MPO activity. Also, blood samples were collected to determine the major organ functional indices. Results Compared to normal controls, HMGB1 mRNA levels were significantly increased in samples from the liver, lungs and kidneys at 2-6h after endotoxin challenge (P<0.05), and the levels remained elevated up to 12h. Meanwhile, serum ALT, AST, BUN, Cr levels as well as pulmonary MPO activity were significantly elevated in the animals following endotoxic shock (P<0.05 or 0.01). Treatment with PDTC could markedly down-regulate HMGB1 mRNA expressions in various organs at 12h compared with endotoxic shock group (P<0.05 or 0.01). In addition, PDTC treatment could significantly reduce serum ALT, AST, BUN, as well as Cr levels at 6h (P<0.05) and MPO activity at 2-12h. Conclusions These data suggest that NF-κB signal transcription pathway may be involved in regulating mRNA expression of HMGB1 in rats after endotoxic shock. Early treatment with NF-κB inhibitors can down-regulate HMGB1 gene expression in vital organs and attenuate endotoxin-induced multiple organ dysfunction.