肿瘤坏死因子受体在多器官衰竭中的表达与基因调控

This study was performed to explore the expression and genetic modulation of tumor necrosis factor receptor(TNFR), and try to explicit the mechanism of TNF-mediated multiple organ dysfunction syndrome(MODS). Some valuable experimental data were presented for the treatment of MODS in clinic. MAIN OBJECTIVES AND CONTENTS: To investigate the protective function of TNFR antagonist on animal models of MODS; to detect the change of transmembrane TNFR and intracellular TNFRmRNA in several major organs after MODS; to detect the change of nuclear factor-kappaB after MODS; to detect the change of the quantity of complex of NF-κB and promotor of TNFR gene after MODS. RESULTS: In this study we succeeded in replicating rat model of MODS by two-hit method. The mobidity and mortality of this model were 100% and 50%, respectively. The traumatic causes, pathogenic progress, clinical features and diagnostic criteria of this model mimicked typical double-phase delayed MODS in clinic. The expression of TNFR1 in livers increased significantly in MODS group in comparison with that in control group(P＜0.05＝. Although the expression of TNFR1 in lungs and kidneys both increased in MODS group, no significant difference was found between MODS group and control group. There was positive correlation between ALT concentration in serum and the expression of TNFR1mRNA in livers, but no correlation existed between BUN concentration in serum and the expression of TNFR1mRNA in kidneys. The mobidity of organ failure with mild and strong expression of NF-κB was 88.89%(40/45), which was significantly higher than that with moderate expression of NF-κB. The expression of NF-κB in several organs, such as liver、lung、kidney and small intestine, in MODS group increased significantly in comparison with that in control group. There was positive correlation between NF-κB and functional index of liver. The quantity of NF-κB in cellular nuclei increased after MODS, which correlated positively with the expression of TNFR and the severity of MODS. After sTNFRp75：Fc was medicated, the activity of TNFa maintained at low level, and the mobidity and mortality of MODS decreased to 43.7% and 12.5%, respectively. The soluble TNFR concentration in serum was 438.06±67.06pg/ml in rat model of MODS, which increased significantly in comparison with the normal level（112.25±24.95pg/ml）. The soluble TNFR concentration in rats with failured organ number equal to or more than 2 were 358.63±17.06pg/ml and 474.18±47.25pg/ml, respectively, and correlated positively with ALT concentration in serum. The study proved that TNF-induced MODS was modulated at the level of receptor, NF-κB took part in the transcription modulation of TNFR, and sTNFRp75：Fc could be used as a treatment of MODS.

在动物多器官衰竭模型上，观察肿瘤坏死因子受体拮抗剂对肿瘤坏死因子的拮抗作用，研究主要衰竭器官细胞肿瘤坏死因子受体数量及活性变化、肿瘤坏死因子受体mRNA表达、核因子-KB以及核因子-KB与肿瘤坏死因子受体基因启动子复合物，以探讨在多器官衰竭中肿瘤坏死因子受体的表达与基因调控，进一步阐明肿瘤坏死因子介导多器官衰竭的作用机理。