本文選題：類風(fēng)濕關(guān)節(jié)炎 + 膠原誘導(dǎo)性關(guān)節(jié)炎　； 參考：《南方醫(yī)科大學(xué)》2017年碩士論文

【摘要】：背景血管新生是類風(fēng)濕關(guān)節(jié)炎(rheumatoid arthritis,RA)的重要特征之一,在RA滑膜血管翳的形成和生長(zhǎng)中起著核心作用,不可控的新生血管形成可以導(dǎo)致炎細(xì)胞浸潤(rùn)、滑膜組織增生,最終導(dǎo)致軟骨和骨破壞,因此延緩或阻斷RA患者的滑膜血管新生已成為RA治療的重要靶點(diǎn)之一。膠原誘導(dǎo)性關(guān)節(jié)炎(collagen-inducedarthritis,CIA)模型的臨床表現(xiàn)、發(fā)病機(jī)理、病理特征等方面與人RA相似,是研究RA的理想動(dòng)物模型。本課題用中藥紅豆杉提取物紫杉醇(taxol,PTX)干預(yù)CIA小鼠,研究PTX對(duì)CIA小鼠滑膜血管新生的作用。目的研究PTX對(duì)CIA小鼠滑膜血管新生及VEGF、HIF-1α表達(dá)的影響。方法用50只C57BL/6(H-2b)小鼠誘導(dǎo)CIA模型,造模后關(guān)節(jié)炎評(píng)分大于4分的CIA 小鼠被隨機(jī)分為 1.5mg/kg PTX 組、1.0mg/kg PTX 組、0.5mg/kg PTX 組及CIA模型組,每組6只,另外6只未造模的正常小鼠作為正常對(duì)照組。干預(yù)組分別予對(duì)應(yīng)劑量的PTX隔日腹腔注射,對(duì)照組予等體積溶媒,共給藥8次。運(yùn)用視覺(jué)模擬評(píng)分法對(duì)小鼠關(guān)節(jié)炎進(jìn)行評(píng)分;HE染色后對(duì)小鼠關(guān)節(jié)組織進(jìn)行病理學(xué)評(píng)分(從滑膜炎、血管翳和骨破壞三個(gè)方面評(píng)估);免疫組化法檢測(cè)關(guān)節(jié)滑膜組織微血管的密度(microvessel density,MVD)以及血管內(nèi)皮生長(zhǎng)因子(vascular endothelial growth factor,VEGF)、低氧誘導(dǎo)因子 1α(hypoxia-inducible factor-α,HIF-1α)的表達(dá);ELISA檢測(cè)小鼠外周血清VEGF和HIF-1α的表達(dá)。結(jié)果PTX干預(yù)組關(guān)節(jié)炎評(píng)分分別為1.33±0.52、2.00±0.63、3.33±1.03,與CIA模型組(5.67±1.03)比較顯著降低,差異均有統(tǒng)計(jì)學(xué)意義(P0.001,P0.001,P=0.016)。PTX干預(yù)組關(guān)節(jié)病理總評(píng)分分別為2.50±0.66、3.89±0.86、6.22±0.98,呈劑量依賴性減少,與CIA模型組(7.67±0.79)比較顯著降低,差異均有統(tǒng)計(jì)學(xué)意義(P0.001,P0.001,P=0.007)。并且PTX能明顯減少(CIA小鼠關(guān)節(jié)病理滑膜炎、血管翳及骨破壞評(píng)分。與CIA模型組(110.32±5.06/mm2)相比,PTX干預(yù)組的MVD亦呈劑量依賴性降低(17.05±1.97/mm2,34.73±2.36/mm2,57.55±2.72/mm2,P均0.001)。此外,1.5mg/kgPTX 組(42.38±3.22)、1.Omg/kg PTX 組(74.30±4.14)、0.5mg/kgPTX 組(121.69±3.81)滑膜組織的 VEGF 表達(dá)低于CIA模型組(156.22±4.75;P均0.001);1.5mg/kg PTX組(19.93±2.92)和1.0mg/kg PTX組(31.99±5.60)的滑膜組織HIF-1α表達(dá)低于CIA模型組(51.10±2.86;P均0.001)。1.5mg/kg PTX 組(10.70±1.21pg/ml)和 1.0mg/kg PTX組(14.75±0.96pg/ml)的外周血清 VEGF 表達(dá)低于 CIA 模型組(16.40±1.43pg/ml,P 均0.001),且 1.5mg/kg PTX 組(2.17±0.43pg/ml)和 1.0mg/kg PTX 組(3.47±0.51pg/ml)外周血清 HIF-1α 表達(dá)亦低于 CIA 模型組(5.07±1.19pg/ml,P0.001,P=0.032)。MVD與關(guān)節(jié)病理滑膜炎、血管翳、骨破壞評(píng)分及滑膜組織VEGF、HIF-1α 的表達(dá)水平均呈正相關(guān)(r=0.921,r=0.944,r=0.889,r=0.969,r=0.933;P均0.001)。結(jié)論P(yáng)TX能抑制CIA小鼠滑膜血管新生,并降低滑膜組織和外周血清VEGF、HIF-1α的表達(dá)水平,PTX可能通過(guò)降低VEGF、HIF-1α的表達(dá)抑制CIA小鼠滑膜血管生成。
[Abstract]:Background Angiogenesis is one of the important characteristics of rheumatoid arthritis (RA), which plays a central role in the formation and growth of synovial pannus. Uncontrolled angiogenesis can lead to inflammatory cell infiltration and synovial tissue proliferation. Finally, cartilage and bone damage are caused, so delaying or blocking synovial angiogenesis in RA patients has become one of the important targets of RA therapy. The collagen-induced arthritis (CIA) model is similar to that of human RA in clinical manifestations, pathogenesis and pathological features. It is an ideal animal model for the study of RA. To study the effect of PTX on synovial angiogenesis in CIA mice, Taxolus taxolatus extract from Taxus cuspidata was used to interfere with CIA mice. Objective to study the effect of PTX on synovial angiogenesis and expression of VEGF HIF-1 偽 in CIA mice. Methods CIA models were induced in 50 C57BL / 6H-2b mice. CIA mice with arthritis score greater than 4 were randomly divided into 1.5mg/kg PTX group (1.0 mg / kg PTX group) and CIA model group (0.5 mg / kg PTX group), with 6 mice in each group and 6 normal mice as normal control group. The intervention group received intraperitoneal injection of corresponding dose of PTX every other day, while the control group received the same volume solvent for 8 times. Using Visual Analog scoring method to score Arthritis in mice with HE staining and pathological grading of Mouse Joint tissue (from synovitis, synovitis, synovitis, synovitis, synovitis, synovitis, The expression of VEGF and HIF-1 偽 in peripheral blood of mice were detected by immunohistochemistry. The expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor (VEGF) and hypoxia-inducible factor- 偽 (HIF-1 偽) were detected by immunohistochemistry. Results the arthritis score of PTX intervention group was 1.33 鹵0.52 鹵0.63 鹵3.33 鹵1.03, which was significantly lower than that of CIA model group (5.67 鹵1.03), and the difference was statistically significant (P 0.001 P 0.001P 0.001P 0.001P 0.016). The total score of joint pathology in PTX-treated group was 2.50 鹵0.663.89 鹵0.866.22 鹵0.98, decreased in a dose-dependent manner, and was significantly lower than that in CIA model group (7.67 鹵0.79). The difference was statistically significant (P 0.001 P 0.001 P 0.001 P 0. 007). And PTX significantly reduced the score of synovitis, pannus and bone destruction in mice. Compared with the CIA model group, MVD in the PTX-treated group decreased in a dose-dependent manner (17.05 鹵1.97 / mm ~ 34.73 鹵2.36 鹵2.36 / mm ~ (-2) 鹵57.55 鹵2.72 / mm ~ (-2) P) in a dose-dependent manner. 姝ゅ,1.5mg/kgPTX 緇，

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