本文選題：大鼠 + 實驗性自身免疫性神經炎　； 參考：《山東大學》2014年碩士論文

【摘要】：研究目的： 吉蘭-巴雷綜合征(Guillain-Barre syndrome, GBS)是以周圍神經髓鞘脫失和小血管炎性細胞浸潤為病理特點的自身免疫性周圍神經病,以肢體對稱性弛緩性癱瘓為主要臨床特征。實驗性自身免疫性神經炎(experimental autoimmune neuritis,EAN)是國際公認的研究GBS的動物模型,是T輔助細胞1和T輔助細胞17(Thl/Th17)介導的自身免疫性疾病,以周圍神經脫髓鞘和大量炎性細胞浸潤為主要病理特點。這些浸潤的炎性細胞主要包括單核巨噬細胞、淋巴細胞以及粒細胞,促炎性細胞因子如IFN-γ、TNF-α、NO及趨化因子MCP-1、MIP-1等在其發(fā)病中起關鍵作用。 近年來研究認為前列腺素E2(Prostaglandin E2)是一種免疫激活劑,可能通過作用于EP4受體影響Thl和Th17這兩個細胞亞群的分化來參與自身免疫性疾病的免疫炎癥過程,由此我們推測PGE2-EP4受體拮抗劑對EAN具有治療作用。在我們的前期研究中發(fā)現(xiàn),應用PGE2-EP4拮抗劑L-161982干預EAN大鼠,可降低其坐骨神經中促炎性細胞因子IL-17及IFN-y的表達�；谮吇蜃釉贕BS/EAN中的重要作用,本實驗觀察了PGE2-EP4拮抗劑L-161982對EAN大鼠趨化因子CXCL-12和MCP-1表達的影響。 實驗方法： 1.用周圍神經鞘磷脂(BPM)免疫Lewis大鼠,制備EAN模型。 2.隨機將21只EAN大鼠分為3組,治療A組、治療B組和對照組。兩個治療組均以劑量為5mg/kg的PGE2-EP4受體拮抗劑L-161982腹腔注射治療。治療A組于免疫階段(免疫前1天至免疫后第8天)每日行L-161982處理,治療B組于發(fā)病階段(免疫后第5天至第14天)每日行L-161982處理。對照組在整個實驗階段每日給予相同體積的L-161982溶媒DMSO腹腔注射。 3.免疫后每日觀察EAN大鼠的臨床評分。于免疫后第15天處死EAN大鼠,取其坐骨神經,用免疫組化法檢測坐骨神經中趨化因子CXCL-12及MCP-1的表達水平。 4.應用SPSS18.0軟件對資料進行統(tǒng)計分析,數(shù)據(jù)以x±s表示。 實驗結果： 1.與對照組相比,不同階段處理的兩個治療組均能延遲EAN的發(fā)病時間(P0.05),降低其高峰期臨床評分(P0.05),減少坐骨神經中CXCL-12和MCP-1的表達(P0.05)。 2.兩個治療組間發(fā)病時間、高峰期臨床評分以及趨化因子表達的比較,均可見顯著差異(P0.05)。 結論： 1.應用L-161982治療可明顯延遲EAN大鼠的發(fā)病時間,降低其高峰期臨床評分,改善EAN大鼠的臨床癥狀,說明其對周圍神經自身免疫性疾病有治療作用。 2.應用L-161982治療可抑制EAN大鼠坐骨神經中趨化因子CXCL-12及MCP-1的表達,提示PGE2-EP4受體拮抗劑L-161982可通過抑制巨噬細胞和T細胞的遷移活化,減少CXCL-12和MCP-1的產生,從而抑制免疫炎癥反應,這可能是L-161982的抗炎機制之一。 3.與發(fā)病階段相比,免疫階段應用PGE2-EP4受體拮抗劑L-161982更能顯著延遲EAN大鼠的發(fā)病時間,降低其高峰期評分,減少坐骨神經中趨化因子CXCL-12和MCP-1的表達。因此,免疫階段使用L-161982治療效果更顯著。
[Abstract]:Objectives of the study: Guillain-Barre syndromeGuillain-Barre syndrome (GBSs) is an autoimmune peripheral neuropathy characterized by peripheral nerve demyelination and small vascular inflammatory cell infiltration. The main clinical feature is limb symmetric flaccid paralysis. Experimental autoimmune neuritis (EAN) is an internationally recognized animal model for the study of GBS. It is an autoimmune disease mediated by T helper cell 1 and T helper cell 17 Thl / Th17. The main pathological features were demyelination of peripheral nerve and infiltration of inflammatory cells. These infiltrating inflammatory cells mainly include mononuclear macrophages, lymphocytes and granulocytes, pro-inflammatory cytokines such as IFN- 緯 -TNF- 偽 no and chemokine MCP-1 / MIP-1, which play a key role in its pathogenesis. In recent years, it has been suggested that prostaglandin E2(Prostaglandin E2 (PGE) is an immune activator, which may be involved in the immune inflammation of autoimmune diseases by affecting the differentiation of Thl and Th17 subsets by acting on EP4 receptors. Therefore, we speculate that PGE2-EP4 receptor antagonist has therapeutic effect on EAN. In our previous study, it was found that PGE2-EP4 antagonist L-161982 could reduce the expression of pro-inflammatory cytokines IL-17 and IFN-y in sciatic nerve of EAN rats. Based on the important role of chemokines in GBS/EAN, the effects of PGE2-EP4 antagonist L-161982 on the expression of chemokines CXCL-12 and MCP-1 in EAN rats were studied. Experimental methods: 1. Lewis rats were immunized with peripheral nerve sphingolipid (BPM) to establish EAN model. 2. Twenty-one EAN rats were randomly divided into three groups: group A, group B and control group. Both groups were treated by intraperitoneal injection of PGE2-EP4 receptor antagonist L-161982 (5mg/kg). Group A was treated daily with L-161982 during the immune phase (from 1 day before immunization to 8 days after immunization) and group B was treated daily with L-161982 at the onset stage (from the 5th to the 14th day after immunization). The control group was given intraperitoneal injection of L-16 1982 solvent DMSO daily during the whole phase of the experiment. 3. The clinical scores of EAN rats were observed daily after immunization. On the 15th day after immunization, EAN rats were killed and their sciatic nerves were removed. The expression of chemokine CXCL-12 and MCP-1 in sciatic nerve was detected by immunohistochemical method. 4. The data were analyzed by SPSS18.0 software, and the data were expressed as x 鹵s. Experimental results: 1. Compared with the control group, the two treatment groups at different stages could delay the onset of EAN, decrease the peak clinical score and decrease the expression of CXCL-12 and MCP-1 in sciatic nerve. 2. There were significant differences in onset time, peak clinical score and chemokine expression between the two groups (P 0.05). Conclusion: 1. L-161982 treatment can significantly delay the onset of EAN rats, reduce its peak clinical score, improve the clinical symptoms of EAN rats, indicating that it has therapeutic effect on peripheral nerve autoimmune diseases. 2. L-161982 treatment could inhibit the expression of chemokine CXCL-12 and MCP-1 in sciatic nerve of EAN rats, suggesting that PGE2-EP4 receptor antagonist L-161982 could inhibit the production of CXCL-12 and MCP-1 by inhibiting the migration and activation of macrophages and T cells. This may be one of the anti-inflammatory mechanisms of L-161982. 3. PGE2-EP4 receptor antagonist L-161982 significantly delayed the onset of EAN rats, decreased its peak score, and reduced the expression of chemokines CXCL-12 and MCP-1 in sciatic nerve. Therefore, the effect of L-161982 was more significant in the immune phase.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R744.5

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