慢性肾功能衰竭低T3与免疫微炎症相关性机制研究

Low serum triiodothyronine (T3) syndrome was widely existed in the patients with chronic renal failure (CRF), and was closely correlated with the microinflammation. However, the exact mechanism which involving with the correlation was unclear. Popular opinions accepted that inflammatory factors such as interleukin 1, interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) could inhibit the message RNA expression of 5' deiodinase (DI) in liver, which can inhibit the conversion from tetraiodothyronine (T4) to T3 outside of the thyroid gland. Recently, researchers displayed that injection of combinant human IL-6 did not change the serum levels of T3 in volunteers. Furthermore, IL-6 and TNF-α did not inhibit the 5'-DI activities of the liver cell line HepG2 in cell cultrues. Therefore, in order to clarify the relationship between inflammatory factors and 5'-DI activities, it is very important to recognize the exact mechanism of the appearance of low serum T3 syndrome in CRF subjects. In our previous study, we found that serum T3 was a good mark for nutritional status of CRF patients in the early or middle stage of this disease. However, with the disease developing, this kind of correlation was prominently displayed in microinflammation. For the sake of explaining the phenomenon, we raised a hypothesis that the relationship between low serum T3 and microinflammation in CRF patients was another kind of "trade off". This study intend to elucidate the relationship between low serum T3 syndrome and microinflammation in CRF patients on levels of cell culture, animal models,to clarify the signal pathways that inflammatory factors inhibiting the activities of 5'-DI of liver cells, and to offer a theoretic evidence for clinical use of thyroxine in these patients.

慢性肾衰竭（CRF）者广泛存在低T3，且与微炎症关系密切，其机制不明。传统观点认为，炎症因子如IL-1、IL- 6和TNF-α等可抑制肝脏5'-脱碘酶（DI）mRNA表达或竞争抑制其共激活剂活性，从而抑制外周T4向T3转变。最近研究显示，受试者注射重组人IL-6并不能改变其外周T3水平；细胞培养也表明，IL-6和TNF-α并不能抑制肝细胞株HepG2 5'-DI活性。因而，阐明炎症因子与5'-DI活性的关系，对了解CRF者低T3的发生机制至关重要。我们前期研究发现，在CRF者早、中期，外周T3反映营养状态。而随疾病进展，这种相关性突出表现在微炎症上。为解释该现象，我们提出CRF者外周T3与微炎症的关系是另一种形式的"矫枉失衡"。 本研究从细胞培养、动物模型及药物试验，探讨CRF低T3综合征与微炎症的关系，阐明炎症因子抑制肝细胞5'-DI活性的信号途径，并为甲状腺激素替代治疗提供理论依据。

尿毒症患者广泛存在非甲状腺疾病综合征(NTIS)且缺乏有效的治疗方案，本研究探讨抗氧化治疗尿毒症大鼠模型NTIS的疗效。结果发现①尿毒症毒素显著抑制DIO1的mRNA表达，且增加炎症因子IL-1β、IL-6及TNF-α的mRNA表达；②尿毒症毒素能 抑制DIO1脱碘活性，其T3转换能力显著下降；尿毒症毒素及特异性siRNA在抑制DIO1脱碘活性方面具有协同效应；③Western blot分析显示，尿毒症毒素可同步降低SelM及DIO1蛋白表达；尿毒症毒素及特异性siRNA在降低SelM及DIO1蛋白表达方面具有叠加效应；④EMSA显示尿毒症毒素可增加NF-κB二聚体及AP-1蛋白的表达，但对CREB-1蛋白无显著影响；特异性siRNA对NF-κB、 AP-1和CREB-1信号蛋白均有显著抑制效应；⑤三种炎症因子中，HepG2细胞分泌IL-6的能力最强，与其mRNA的表达一致；与对照组相比，尿毒症毒素组培养上清中IL-6显著升高，也高于siRNA组，但与尿毒症毒素和siRNA协同作用组无显著差异，这可能和HepG2细胞分泌IL-6能力较强，而特异性siRNA效应相对较弱有关。动物模型研究结果发现：与5/6 Nx组相比，PDTC和NAC组的血清MDA、AOPP、TSH水平均显著降低，血清SOD及FT3水平增高，而这两组血清IL-1β水平均没有显著统计学意义，但显著减少IL-1β的蛋白表达，增加DIO1的蛋白表达，且这两组均极大程度地抑制NF-κB活性。科学意义：研究首次证实尿毒症毒素对HepG2细胞分泌炎症因子的刺激作用，且抑制肝细胞脱碘酶DIO1活性；而DIO1活性下降后对炎症因子的抑制，可能是CKD患者NTIS状态下的自身反馈调节，以避免多种因素下炎症因子和氧化应激产生瀑布效应。在尿毒症大鼠模型中，PDTC和NAC治疗组均能有效地改善氧化应激水平及NTIS状态，而就改善尿毒症大鼠氧化应激水平而言，NAC组更优于PDTC组。

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