本文選題：克羅恩病 + 雷公藤多苷��； 參考：《南京大學(xué)》2014年碩士論文

【摘要】：背景：克羅恩病(Crohn's disease, CD)屬于炎癥性腸病(inflammatory bowel disease,IBD)的一種,近一個(gè)世紀(jì)以來其發(fā)病率越來越高。盡管相關(guān)研究逐漸深入,但其確切病因至今仍然不清。目前認(rèn)為其病因涉及基因易感性、環(huán)境因素、免疫因素。表達(dá)叉狀頭／翅膀狀螺旋轉(zhuǎn)錄因子(Forkhead Box P3, Foxp3)的調(diào)節(jié)性T細(xì)胞(t regulatory cells, Tregs)通過分泌IL-10、TGF-β發(fā)揮抑炎作用,在維持機(jī)體免疫穩(wěn)態(tài)方面發(fā)揮重要作用。許多研究發(fā)現(xiàn)Tregs與CD發(fā)病之間存在相關(guān)性。雷公藤多苷提取自中國(guó)一味傳統(tǒng)中藥雷公藤的根部,具有抗炎、免疫調(diào)節(jié)、抗腫瘤等作用。在中國(guó),雷公藤多苷被廣泛用于治療多種自身免疫性疾病,包括類風(fēng)濕關(guān)節(jié)炎、腎炎及系統(tǒng)性紅斑狼瘡等。雷公藤能夠緩解結(jié)腸炎小鼠的腸道炎癥,其作用機(jī)制包括抑制TLRs/NF-κB和TNF-α/TNFR2信號(hào)通路,抑制L-6/STAT3通路、下調(diào)IL-17表達(dá)。我們之前研究證實(shí),雷公藤多苷能夠有效誘導(dǎo)CD緩解。但其具體機(jī)制尚未明確。目的： 探索雷公藤多苷對(duì)CD病人腸道粘膜局部炎癥因子表達(dá)及Foxp3+ Tregs水平的作用。方法：從南京軍區(qū)南京總醫(yī)院門診部入選處于中重度活動(dòng)期的CD病人,給予口服雷公藤多苷片60mg／天(中國(guó)江蘇,泰州制藥廠)。入選時(shí)及三個(gè)月后行結(jié)腸鏡檢查,于病變明顯的同一段腸管鉗取6塊腸粘膜。HE染色后使用光鏡觀察腸粘膜病理變化并進(jìn)行炎癥浸潤(rùn)程度的評(píng)分；采用免疫組化法檢測(cè)病變腸粘膜中Foxp3、IL-10、TNF-α的表達(dá)變化；采用免疫印跡(Western blot)檢測(cè)Foxp3蛋白表達(dá)的變化；采用酶聯(lián)免疫吸附法(ELISA)測(cè)定病變腸道粘膜中炎癥因子IL-10、TNF-α水平變化。結(jié)果： 20個(gè)CD病人參與了本項(xiàng)研究,年齡介于25-57歲之間。其中8個(gè)病人疾病處于輕度活動(dòng)期,另外12個(gè)病人疾病處于中度活動(dòng)期。所有人均接受了三個(gè)月的口服雷公藤多苷片治療,沒有人因?yàn)榧膊〔涣挤磻?yīng)而退出實(shí)驗(yàn)。治療前的病變腸粘膜HE病理可見潰瘍、上皮損害、腺體減少和炎癥細(xì)胞的浸潤(rùn),而接受三個(gè)月雷公藤多苷片治療后,鏡下病理明顯改善。治療后的炎癥浸潤(rùn)程度評(píng)分顯著降低(8.1±2.2 vs 6.8±2.6,P0.05)。免疫組化的結(jié)果表明,雷公藤治療后,腸粘膜中Foxp3+ Tregs和IL-10陽性細(xì)胞的水平呈現(xiàn)增多趨勢(shì),而促炎因子TNF-α則呈現(xiàn)下調(diào)趨勢(shì)。Western blot檢測(cè)顯示,治療前病變腸粘膜中Foxp3蛋白有一定的表達(dá),而雷公藤多苷治療后,Foxp3蛋白能夠進(jìn)一步上調(diào)。在炎癥因子表達(dá)方面,雷公藤多苷使促炎因子TNF-α水平顯著下降(189.6±17.4 vs173.0±19.0,P0.01),而抑炎因子IL-10的水平顯著上升(45.7±16.3 vs 55.6±14.8,P0.05)。結(jié)論：雷公藤多苷能夠緩解CD病變腸管的炎癥,改善局部粘膜的病理損害,調(diào)節(jié)局部免疫環(huán)境的炎癥因子的表達(dá)水平,使促炎因子TNF-1α水平下降,抑炎因子IL-10的水平上升,其作用機(jī)制可能和病變腸管中Foxp3+ Tregs增多有關(guān)。
[Abstract]:Background: Crohn's disease (CDD) is a kind of inflammatory bowel disease. The exact cause of the disease is still unclear, although the relevant studies have gradually deepened. It is believed that the etiology is related to genetic susceptibility, environmental factors and immune factors. Regulatory T cell regulatory cells, Tregs), which expresses Forkhead Box P3 (Foxp3), plays an important role in maintaining immune homeostasis by secreting IL-10 TGF- 尾. Many studies have found a correlation between Tregs and CD. Tripterygium wilfordii polyglycosides extracted from the roots of traditional Chinese medicine Tripterygium wilfordii have anti-inflammatory, immunomodulatory and anti-tumor effects. In China, tripterygium wilfordii polyglycosides are widely used in the treatment of many autoimmune diseases, including rheumatoid arthritis, nephritis and systemic lupus erythematosus. Tripterygium wilfordii can relieve intestinal inflammation in mice with colitis by inhibiting TLRs / NF- 魏 B and TNF- 偽 / TNFR2 signaling pathway, inhibiting L-6/STAT3 pathway and down-regulating IL-17 expression. Our previous studies have confirmed that triptolide can effectively induce CD remission. But its specific mechanism is not clear. Objective: to investigate the effect of tripterygium wilfordii polyglycoside on the expression of local inflammatory factors and the level of Foxp3 Tregs in intestinal mucosa of CD patients. Methods: CD patients were selected from the outpatient department of Nanjing General Hospital of Nanjing military region and given oral Tripterygium wilfordii polyglycoside tablets for 60mg/ days (Taizhou Pharmaceutical Factory, Jiangsu, China). Colonoscopy was performed at the time of selection and after 3 months. After 6 intestinal mucosa was stained with HE, the pathological changes of intestinal mucosa were observed with light microscope and the degree of inflammatory infiltration was evaluated. The expression of Foxp3hIL-10 TNF- 偽 was detected by immunohistochemistry, the expression of Foxp3 protein was detected by Western blot, and the level of IL-10TNF- 偽 in intestinal mucosa was detected by enzyme-linked immunosorbent assay (Elisa). Results: twenty CD patients, aged 25-57, participated in the study. Among them, 8 patients had mild active disease and 12 patients had moderate active disease. All were treated with oral tripterygium wilfordii for three months, and no one dropped out because of adverse effects. The pathological changes of intestinal mucosa before treatment were ulcer, epithelial damage, decreased glands and infiltration of inflammatory cells. After three months of treatment with tripterygium wilfordii polyglycosides, the pathological changes were obviously improved under microscope. After treatment, the score of inflammatory infiltration decreased significantly (8.1 鹵2.2 vs 6.8 鹵2.6 P 0.05). The results of immunohistochemistry showed that the levels of Foxp3 Tregs and IL-10 positive cells in intestinal mucosa increased after Tripterygium wilfordii treatment, while the levels of TNF- 偽 were down-regulated. Western blot showed that TNF- 偽 was down-regulated. Foxp3 protein was expressed in intestinal mucosa before treatment, but Foxp3 protein was upregulated further after triptolide was treated with tripterygium wilfordii. In terms of inflammatory factor expression, tripterygium wilfordii polyglycoside significantly decreased the level of proinflammatory factor TNF- 偽 by 189.6 鹵17.4 vs173.0 鹵19.0U P0.01g, while the level of IL-10 increased significantly by 45.7 鹵16.3 vs 55.6 鹵14.8P0.05a. Conclusion: Tripterygium wilfordii polyglycoside can alleviate the inflammation of intestinal canal of CD lesion, improve the pathological damage of local mucosa, regulate the expression of inflammatory factor in local immune environment, decrease the level of proinflammatory factor TNF-1 偽 and increase the level of IL-10. The mechanism may be related to the increase of Foxp3 Tregs in the diseased intestine.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R574.62

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