反义TNF-α寡脱氧核苷酸降低多器官功能不全综合征大鼠死亡率

Antisense TNF-α oligodeoxynucleotide decreases mortality in multiple organ dysfunction syndrome mice

目的 观察反义肿瘤坏死因子 -α(tumornecrosisfactor -alpha ,TNF -α)寡脱氧核苷酸对酵母多糖A(zymosanA)诱导的多器官功能不全综合征 (multipleorgandysfunctionsyndrome ,MODS)大鼠的影响 ,探讨MODS的发病机制 ,为采用反义技术降低MODS死亡率的早期临床试验提供实验依据。方法 采用静脉注射方法 ,使反义TNF -α寡脱氧核苷酸 (ODN)作用于zymosanA诱导的MODS大鼠 :①采用RT -PCR ,ELISA检测大鼠肝TNF -α的mRNA和蛋白质的表达水平 ;②观察大鼠在不同时期的死亡率 ;③在zymosanA诱导大鼠MODS 2 4小时后采集股动脉血进行血气分析 ,采集外周血进行血清生化检测 ,并进行统计学分析。结果 反义TNF -αODN降低了zymosanA诱导的MODS大鼠的TNF -α的释放 ,降低了MODS大鼠的死亡率 ,而正义TNF -αODN和错配TNF -αODN与对照组相比 ,对TNF -α的释放无影响 ,未能降低MODS大鼠的死亡率。结论 反义TNF -αODN以序列特异性方式抑制了zymosanA诱导的MODS大鼠的TNF -α的释放 。

Objective To evaluate the effect of antisense phosphrothioate tumor necrosis factor-alhpa(TNF-α) oligodeoxynucleotide(ODN) on mortality in multiple organ dysfunction syndrome(MODS) rat induced by zymosan A. The investigation provides the basis for the early clinical trials assessing the therapeutic potential of antisense TNF-α approach for decreasing death rate in MODS.Methods MODS rat model was induced by intraperitoneal injection zymosan A. Rat antisense TNF-α ODN was applied to the reticular-endotheial system in MODS SD rat RT-PCR was used to detect rat liver TNF-α mRNA. pH,PaCO a and PaO 2 from artarial blood and LDH, ALT, Cr and TNF-α from venous blood were monitored after zymosan A induced MODS.Results The antisense TNF-α ODN can suppress release of TNF-α and reduce mortality in MODS rat induced by zymosan A, but sense or mismatched TNF-α ODN can′t.Conclusions The results suggest antisense TNF-α ODN significantly suppressed production of TNF-α in MODS. The investigation provides the basis for the early clinical trials assessing the therapeutic potential of antisense TNF-α approach for decreasing death rate in MODS.