臺灣博碩士論文加值系統

在脊髓損傷發生後，有許多未知的複雜機制會影響微小膠細胞與巨噬細胞的活化作用，而對於中樞神經系統則可能有更進一步的影響。先前本實驗室在研究動物神經修復模式(a combination of peripheral nerve grafts with acidic fibroblast growth factor [aFGF] treatment)中發現在脊髓神經修復初期會有大量的巨噬細胞被活化，並且伴隨有明顯的arginase I表現以及polyamines的產生，但是對於其中與神經修復的相關連性之機制與影響未知。本研究利用體外細胞培養的方式來探討在不同的活化途徑之下活化的巨噬細胞所表現的arginase I和多胺素的變化情形，以及利用在動物脊髓神經修復模式中給予多胺素生合成酵素的抑制劑，長期觀察神經損傷處的巨噬細胞對神經修復的影響，以期可供解開中樞神經系統修復中複雜機制之一環。
實驗結果顯示藉由IL-4誘導之下，可以將巨噬細胞株活化成alternatively activation type，而LPS或是IL-1b + TNFa + INFg則無法誘導巨噬細胞株表現arginase I。在經由IL-4、IL-1b + TNFa + INFg、LPS或是合併aFGF等處理的活化方式下，活化的巨噬細胞其下游的訊息傳導路徑分別會有不同程度被磷酸化蛋白質的表現。而在單獨處理aFGF不會表現arginase I或是iNOS；在合併aFGF處理之下，經由IL-4、IL-1b + TNFa + INFg以及LPS的活化方式分別不會影響其表現arginase I或是iNOS。在mRNA表現方面，藉由IL-4誘導活化6小時後，在合成polyamines路徑中的spermidine synthase有提高的現象。經IL-4或有無合併aFGF誘導活化6到48小時後，相較於同時間點之其他組別在合成polyamines路徑中的arginase I有提高的現象；然而在LPS和IL-1b + TNFa + IFNg誘導經24小時或是12小時之下，arginase II或ornithine decarboxylase則會上升。經IL-1b + TNFa + IFNg或有無合併aFGF誘導活化6到48小時後，相較於同時間點之其他組別在合成polyamines路徑中的iNOS有提高的現象。在HPLC分析結果顯示經由IL-4 + aFGF誘導釋放到細胞外多胺素之含量在24和48小時相較於LPS會有明顯提高。在動物實驗後的長期行為模式觀察下，給予阻斷多胺素生合成酵素活性的抑制劑後，會阻礙動物行為的恢復。這些結果顯示多胺素對於本脊髓神經修復的策略，可能是其中一個必要影響的要素。而這些具有alternatively activation type類型的活化巨噬細胞可能對於在脊髓神經修復或是神經再生有重要的影響。

Many complicated mechanisms affect the activation of microglia and macrophage after the spinal cord injury and influence the outcome of recovery. Our preliminary data showed large numbers of activated macrophages were recruited in spinal cords after a repair strategy of peripheral nerve grafts with acidic fibroblast growth factor (aFGF) treatment. In addition, the expression of arginase I (Arg I) and polyamines were significantly upregulated in repaired spinal cords. These findings indicated that some molecular mechanisms triggered by the full repair procedure in the early stage of spinal cord injury may be important to functional recovery.In this study, we investigated the expression patterns of Arg I and polyamines in in vitro macrophage culture and in vivo animal models.
Western blotting analysis showed that IL-4 (10 ng/ml) can stimulate macrophage cell line, RAW 264.7, to arginase I-positive alternatively activated macrophages but not LPS (1 mg/ml) or IL-1b + TNFa + INFg. IL-4、LPS and IL-1b + TNFa + INFg along or combined with aFGF (50 ng/ml) induced different level of phosphorylated proteins expression in signaling pathways of activated macrophage. aFGF alone can't significantly induce arginase I and iNOS expression in macrophages and there were no synergistic effects on the expression of arginase I and iNOS when IL-4、LPS or IL-1b + TNFa + INFg combined with aFGF treatment. Q-PCR results showed that, 6 hours after stimulation, combination of aFGF, IL-4 induced spermidine synthase mRNA expression. 6 to 48 hours after stimulation, with/without combination of aFGF, IL-4 induced arginase I mRNA expression, compared with the same time groups. LPS or IL-1b + TNFa + IFNg induce arginase II or ornithine decarboxylase mRNA expression in 24 or 12 hours. 6 to 48 hours after stimulation, with/without combination of aFGF, IL-1b + TNFa + IFNg induced iNOS mRNA expression, compared with the same time groups. HPLC analysis results show that polyamines released by combination of aFGF, IL-4 induced macrophages were higher than LPS induced macrophages after 24 and 48 hr stimulation. Addition of arginase I and ornithine carboxylase inhibitors (such as nor-NOHA and DFMO) in repaired spinal cords reduced the recovery of animal behavior after 8 weeks long-term observation. These data revealed that the expression of polyamines would be an essential key element for our repair strategy. Alternatively activated macrophages were suggested to be important to spinal cord repair and neural regeneration.

圖目錄…………………………………………………………………….………….III
中文摘要………………………………………………..…………………….………V
英文摘要…………………………………………………………………...………...VI
研究背景簡介…………………………………………………………………………1
研究目的與動機……………………………………………………………………..16
研究策略……………………………………………………………………………..17
研究方法與步驟……………………………………………………………………..19
實驗結果……………………………………………………………………………..31
在無血清之RPMI-1640培養液中，經由IL-4活化RAW264.7細胞後表現arginaseI………………………………………………………………………….31
藉由IL-4誘導之下，可以將巨噬細胞活化成alternatively activation type，而LPS則無法誘導巨噬細胞株表現arginaseI…………………………………….32
aFGF無法誘導巨噬細胞株表現arginase I或iNOS………………………..…32
合併aFGF與IL-4，或aFGF與LPS的處理，影響巨噬細胞細胞表現arginase I或是iNOS………………………………………………………………………33
巨噬細胞經由不同的活化方式，在合成多胺素路徑中的酵素又不同程度之mRNA表現………………………………………………………………………34
巨噬細胞經由IL-4、LPS或aFGF等不同活化方式處理後，其下游被磷酸化蛋白質有不同程度的表現………………………………………………………35
在動物脊髓神經損傷與修復模式之損傷區與移植區會釋放出不同含量的多胺素…………………………………………………………………………………35
在動物實驗後的長期行為模式觀察下，給予阻斷多胺素生合成酵素活性的抑制劑後，對於動物行為恢復模式有降低的效果……………………………….36
結論……………………………………………………………………………...…...37
討論…………………………………………………………………………………..38
結果圖表……………………………………………………………………………..47
參考文獻……………………………………………………………………………..66
附錄…………………………………………………………………………………..78

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