ASIC3基因的剔除調控M1/M2巨噬細胞比例以減緩坐骨神經慢性壓迫性損傷所誘發的熱痛覺過敏

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黃翊筑(Yi-Chu Huang) 查詢紙本館藏

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生命科學系

論文名稱

ASIC3基因的剔除調控M1/M2巨噬細胞比例以減緩坐骨神經慢性壓迫性損傷所誘發的熱痛覺過敏
(ASIC3 gene deletion modulates M1/M2 macrophage ratio to attenuate thermal hyperalgesia induced by chronic constriction injury of the sciatic nerve)

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摘要(中)

神經病變性疼痛是由神經系統中的原發病變或功能障礙引發或引起的疼痛。症狀包括自發性疼痛，感覺異常，感覺異常，異常性疼痛和痛覺過敏。神經病變性疼痛通常伴隨神經炎症，免疫反應，衛星神經膠質細胞 (Satellite glial cells, SGCs) 激活和神經元損失。局部組織酸中毒是調節發炎反應和誘發疼痛的主要因素。酸敏感離子通道3 (Acid-sensing ion channel 3, ASIC3) 是質子傳感受體之一，直接或間接地介導疼痛和痛覺過敏反應。然而，ASIC3參與神經病變性疼痛的相關機制尚不清楚。我已經建立了坐骨神經慢性壓迫性損傷模型（Chronic constriction injury, CCI），以探討ASIC3在神經性疼痛中的作用。我發現CCI小鼠出現了長期的機械性和熱痛覺過敏反應。ASIC3-/-小鼠從第一周開始減緩由CCI誘導的長期熱痛覺過敏，並且抑制效果維持在14W。組織化學分析顯示在CCI小鼠的受損神經中顆粒性細胞和巨噬細胞引發長期神經發炎反應。在ASIC3-/-小鼠中，巨噬細胞的總數在術後第一周增加但在第4、8周時減少。我發現剔除ASIC3基因減少了促炎性巨噬細胞（M1）的數量，但增加了抗炎症巨噬細胞（M2）的數量。因此，從我的實驗結果可以推論ASIC3可能藉由調控M1/M2巨噬細胞的比例來參與在外週神經損傷誘導的熱痛覺過敏。

摘要(英)

Neuropathic pain is a pain initiated or caused by a primary lesion or dysfunction in the nervous system. Symptoms include spontaneous pain, dysaesthesia, paraesthesia, allodynia and hyperalgesia. Neuropathic pain often accompanies with neuroinflammation, immune responses, satellite glial cells (SGCs) activation and neuron loss. Local tissue acidosis is a major factor to regulate inflammation and induce pain. Acid-sensing ion channel 3 (ASIC3), one of proton-sensing receptors, directly or indirectly mediates pain and hyperalgesia. However, it remains unclear whether is involved in neuropathic pain. I have established a model chronic constriction injury of sciatic nerves (CCI) to explore the role of ASIC3 in neuropathic pain. I have found that CCI mice developed long-term mechanical hyperalgesia and thermal hyperalgesia. In ASIC3-/- mice, the long-term thermal hyperalgesia induced by CCI was reduced from the first week and the inhibitory effect was maintained for 14W. Histochemistry analysis of injured nerve demonstrated that CCI mice developed long-term inflammation with granulocytes and macrophages. In ASIC3-/- mice, the number of macrophages were significantly increased compared to ASIC3+/+ at the first week but decreased at 4, 8W. I have found that ASIC3 deletion decreased the number of pro-inflamatory macrophage (M1), but increased the number of anti-inflamatory macrophage (M2) after CCI surgery. Accordingly, ASIC3 may involve in thermal hyperalgesia induced by peripheral nerve injury via modulates the proportion of M1 / M2 macrophages ratio.

關鍵字(中)

★ ASIC3
★ 神經病變性疼痛
★ 巨噬細胞
★ 熱痛覺過敏
★ CCI

關鍵字(英)

論文目次

第一章緒論 1
1.1 神經病變性疼痛 (Neuropathic pain) 2
1.2 瓦勒式退化反應 (Wallerian degeneration) 3
1.3 神經發炎反應 (Neuroinflammatin) 4
1.3.2 衛星膠細胞 (Satellite glial cells, SGCs) 在神經損傷中的角色 6
1.3 酸敏感受體 (Proton-sensing receptors) 7
1.4 研究動機與目的 8
第二章材料與方法 9
2.1 實驗材料 10
2.1.1 實驗動物 (Experimental animal) 10
2.1.2 實驗藥品 (Experimental drugs) 10
2.1.3 實驗器具 (Experimental tools) 11
2.2 實驗方法 (Experimental methods) 11
2.2.1 小鼠基因型判定 (Genotyping) 11
2.2.2 坐骨神經慢性壓迫性損傷引發神經病變性疼痛模式 (Chronic contraction injury of sciatic nerve model, CCI model) 12
2.2.3 痛覺行為測試 (pain behavioral tests) 13
2.2.4 蘇木素-伊紅染色 (Hematoxyline and Eosin stain, H&E stain) 14
2.2.5免疫組織化學染色法 (Immunohistochemistry-Paraffin stain, IHC-P stain) 14
2.2.6 免疫組織化學螢光染色法 (Immunohistochemistry stain, IHC stain) 15
2.3 統計分析 (Statistics) 15
第三章結果 16
3.1 坐骨神經慢性壓迫性損傷引發機械性痛覺及熱痛覺過敏現象 17
3.2 TDAG8不參與在CCI所引發熱痛覺過敏感現象 18
3.3 TRPV1剔除的小鼠減緩第1週由CCI所造成的熱痛覺過敏感現象 18
3.4 ASIC3剔除的小鼠抑制由CCI所造成的熱痛覺過敏感現象 19
3.5坐骨神經慢性壓迫性損傷增加星膠細胞 (Satellite glial cells, SGCs) 表現 19
3.6 ASIC3基因剔除不會減少CCI 動物模型的衛星膠細胞 (SGCs) 表現 20
3.7 ASIC3基因剔除改變坐骨神經損傷部位免疫細胞的表現 20
3.8 ASIC3基因剔除降低M1巨噬細胞但增加M2巨噬細胞數量 22
3.9 腹腔注射Amiloride在WT 小鼠CCI 動物模型抑制機械性痛覺過敏感現象 23
第四章討論 25
4.1 慢性壓迫損傷模型誘發機械性及熱痛覺過敏 26
4.2 ASIC3參與調控CCI動物模型所引起的熱痛覺過敏感現象 27
4.3 CCI 動物模型影響衛星膠細胞 (SGCs) 的活化 27
4.4 ASIC3參與調控坐骨神經損傷部位M1及M2巨噬細胞的數量 28
4.5 Amiloride 抑制由CCI引發的機械性痛覺過敏感現象並改變免疫細胞數量 29
4.6 總結 30
第五章參考文獻 31
附錄I (引子序列) 59
附錄II (實驗藥品、溶劑及藥劑配方) 60

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指導教授

孫維欣(Wei-Hsin Sun)

審核日期

2019-1-17

推文