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糖皮质激素对人中性粒细胞脱颗粒快速抑制作用及其分子机制及研究.pdf 47页
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糖皮质激素对人中性粒细胞脱颗粒的快速抑制作用及分子机制研究
节免疫、代谢、生长发育等多种生理和药理作用，并参与行为和认知过程的调节。糖
皮质激素可以通过基因组和非基因组两种机制发挥作用。与基因组效应相比，GCs
的非基因组效应具有以下特点：a．效应发生的时间短，恢复快(数秒到数分)；b．效应
不能被转录／蛋白合成抑制剂或类固醇激素受体拮抗剂所阻断；c．偶联某些大分子物质
(如BSA)不能通过细胞膜的糖皮质激素，也可以发生的效应；d．在缺少细胞核或不
能进行RNA和蛋白质合成的细胞内(如红细胞、精子、培养的胚胎海马神经元)也可
以发生的效应；e．糖皮质激素与不具有激活转录活性的突变受体结合后仍能发挥的
效应。GCs基因组作用的机制目前已经有了较深入的研究，但对非基因组机制的了解
大多还只停留在快速效应现象上，对于非基因组效应的分子机制目前并不是十分明
p38、PKC、cAMP、IP3等，作用于不同的细胞机制并不一样。
中性粒细胞(neutrophil，又称多形核白细胞，polymorphonuclear
是人体内非常重要的免疫细胞，是宿主防疫外来病原入侵的第一道防线。PMN被活
化后，主要通过呼吸爆发(释放氧自由基)和脱颗粒(释放多种蛋白水解酶)发挥杀
菌功能。但当PMN激活过度时，又能导致组织损伤、引发很多的疾病，比如类风湿
性关节炎、缺血再灌注损伤、慢性阻塞性肺疾病、哮喘等等。而抑制中性粒细胞的过
度活化可以改善这些炎性疾病，大剂量糖皮质激素是治疗这类严重炎性疾病的重要手
段，我们推测大剂量的GCs可能是通过抑制PMN的过度激活来发挥作用的。我们前
期的实验验证了这一推测，体外大剂量的能在五分钟内快速抑制中性粒细胞脱颗粒，
用GCs核受体拮抗剂RU486和转录／蛋白合成抑制剂放线菌酮均不能阻断这种效应，
提示糖皮质激素的这种抑制效应是通过非基因组机制起作用。
PMN脱颗粒的机制非常复杂，不同刺激物的信号转导途径并不一样，同一刺激
物也可以通过多条途径激发细胞脱颗粒，不同途径之间又相互影响和联系，形成一个
脱颗粒主要通过以下几条途径：(1)受体酪氨酸激酶信号转导途径；(2)磷脂酶一PKC
第二军医大学硕士学位论文
(5)PKB信号转导途径等等。
cAMP是调节PMN活性的非常重要的第二信使。研究证明，升高胞内cAMP水平
体、G蛋白和AC三种蛋白质，胞外刺激性信号或抑制性信号与刺激性或者抑制性受
白磷酸化，进而调节细胞反应，不同细胞PKA的底物蛋白不同，所以产生的效应也不
同。cAMP很快被PDE分解，信号被灭活。PDE共分为九型，在不同的组织和细胞中
都有表达，不同组织和细胞的PDE亚型不一样。cAMP专一的PDE亚型是第四亚型，
PDE4又分为四个亚型，分别为A、B、C、D亚型，每个亚型由不同的基因表达。人
中性粒细胞和单核细胞主要表达PDE
物酶和乳铁蛋白，采用放免法检测PMN胞内cAMP水平，用比色法测定PDE活性，探
讨GCs抑制人PMN脱颗粒的信号通路及其作用的靶点。检测了GCs预处理五分钟以及
13对GCs抑制伽LP刺激的PMN脱颗粒的影响；用甲基．B．环糊精破坏细胞膜脂筏
主要取得了以下结果：
1．GCs可显著升高PMN胞内cAMP水平；
3．PMN经化学穿孔后，兴奋性G蛋白(Gs)阻断剂GDPS不能逆转GCs对PMN
脱颗粒的抑制作用；
4．fMLP增强PMN的PDE活性，GCs抑制PMN的PDE活性；
5．甲基．B一环糊精(Methyl．13一cyclodextrin，MCD)不能逆转GCs对PMN脱颗粒的
抑制作用。
糖皮质激素对人中性粒细胞脱颗粒的快速抑制作用及分子机制研究
综上可以发现，大剂量糖皮质激素抑制人外周血中性粒细胞脱颗粒的信号通路之
用，这种非基因组作用不是作用于细胞膜上兴奋性G蛋白偶联受体或者胞内经典的
GCR，也可能不是作用在细胞膜脂筏结构。
关键词：中性粒细胞，糖皮质激素，脱颗粒，非基因组作用，cAMP，PDE
第二军医大学硕．L学位论文
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糖皮质激素诱导移植耐受的免疫细胞调控效应及机制Immunomodulation and Mechanism of Transplantation
Immune Tolerance Induced by Glucocorticoids
DOI: , PP. 5-10
Keywords: 糖皮质激素；T细胞发育、分化；免疫稳态；免疫调节Glucocorticoid,,,
糖皮质激素(G GC)是强有效的甾体类抗炎药和免疫抑制剂，在重症感染、休克、自身免疫病和器官移植等疾病中广泛应用。在器官移植领域GC一直发挥着基础性作用，它是器官移植围手术期免疫诱导必不可少的药物，是经典免疫抑制维持三联方案的重要组成部分，也是治疗急性排斥的首选用药。其作用广泛，能调节代谢、细胞发育和分化；作用机制复杂，不仅有经典的细胞核糖皮质激素受体(glu GCR)信号通路调节DNA的转录，还有其他多种快速作用机制调节细胞功能。本文对GC诱导移植免疫耐受的免疫细胞学调控效应及其机制做以简要综述。
Glucocorticoids (GCs) are potent steroidal anti-inflammatory drugs and immunosuppressants, which are widely used in severe infection, shock, autoimmune diseases, organ transplantation and other diseases. GCs have played a fundamental role in the field of organ transplantation, including induction of immune tolerance, maintenance of immunosuppression and therapy for graft rejection. They act on various cells, and regulate metabolism, cell growth and differentiation. The modulatory mechanisms of GCs are very complex. Through the classic cytoplasmic glucocorticoid receptor (GCR) signaling pathway, it can regulate the transcription of DNA. And, it also has rapid effects on immunity via non-genomic mechanisms. This review summarized the current progresses of immunomodulation and mechanisms of glucocorticoids on the transplantation immune tolerance.
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