摘　要
研究目的：脊髓缺血性損傷對於在接受主動脈手術的病人來講是一個很嚴重的併發症，在脊髓缺血再灌流的過程中，缺血前處理有保護脊髓的功能，本研究希望能夠了解運用缺血前處理來減少脊髓缺血性損傷時，究竟是經由何種機制產生保護的作用，並且研究脊髓的自主調節系統，是否占有重要的地位。另外，在extracellular signal-regulated kinases 1 and 2 (ERK1/2)的研究中，認為ERK1/2與細胞存活與分化有關，但是有越來越多的證據證實，ERK1/2這條路徑跟缺血再灌流損傷的發炎反應有重要的關連。本研究將研究缺血前處理是否啟動脊髓的自主調節系統，以及阻斷ERK1/2路徑是否減少發炎反應，經由控制這兩種機制是否可以減少脊髓缺血性損傷。
研究方法：第一部分的實驗中，將大白鼠(Sprague-Dawley rat)分成4組，一組是缺血前處理(P)組，一組是缺血再灌流損傷(I/R)組，一組是缺血性前處理之後再加上缺血再灌流損傷(P+I/R)組，最後一組是對照(S)組。我們評估這4組的大白鼠的神經學功能，脊髓的病理切片，局部脊髓血流，以及局部的組織氧壓力濃度。在第二部分的實驗中，大白鼠分成三組，第一組是對照組(DSMO組)，只給予dimethyl sulfoxide (DSMO)作為治療藥物，第二組是U0126作為治療藥物(U0126組)，實驗動物將給予mitogen-activated protein kinase (MAPK)/ERK1/2的抑制劑U0126來抑制ERK1/2的磷酸化情形。第三組是對照組。我們評估神經學功能、神經細胞存活數量，發炎反應的狀況以及interleukin 1β(IL-1β)的產生。
結果：第一部分的實驗中，(I/R)組，與(S)組、(P)組以及(P+I/R)組，這三組比起來，(I/R)組有明顯的比較差的神經學功能。由存活的神經運動細胞的數量來看，比起(I/R)組而言，可以看到(P)組，(S)組以及(P+I/R)組都有比較多的存活運動神經元。在脊髓局部的血流以及組織氧壓力濃度的實驗中可以發現，(P)組跟(S)組比起來，(P)組有比較高的脊髓局部的血流以及組織氧壓力濃度，而(P+I/R)組和比(I/R)組比起來，(P+I/R)組有比較好的脊髓局部的血流以及組織氧壓力濃度。在第二部分的實驗中，發現早期的ERK1/2的磷酸化情形，在DSMO組有明顯的上升，而且還併有微小膠質細胞的聚集，並且會增加IL-1β的表現。在U0126組，給予U1026治療後可以抑制ERK1/2的磷酸化，微小膠質細胞的活化及脊髓的IL-1β也有明顯的減少，同時神經細胞存活數量及神經功能的表現也有明顯改善。
結論：給予缺血前處理的話可以減少脊髓缺血再灌流損傷，可能的因素之一是啟動脊髓的自主調節系統，而改善了脊髓的局部血液循環以及組織氧壓力濃度。另外，U0126可以有效抑制ERK1/2路徑，減少微小膠質細胞的浸潤及IL-1β的產生，進而改善神經細胞的存活及功能的保存。ERK1/2路徑在脊髓缺血再灌流損傷似乎扮演發炎反應調控者的重要角色。運用這些研究成果，希望進一步的研究成果可能在未來有臨床使用的機會。

Objective: Ischemic spinal cord injury is a serious complication of aortic surgery. The mechanism underlying ischemic preconditioning (IPC) protection against spinal cord ischemia/reperfusion (I/R) injury is unclear. We investigated the role of spinal cord autoregulation in tolerance to spinal cord I/R injury induced by IPC. Although the extracellular signal-regulated kinases 1 and 2 (ERK1/2) are generally regarded as related to cell survival and proliferation, increasing evidence suggests that the role of the ERK1/2 pathway in I/R injury is contributory to inflammation. We investigated the effect of blocking ERK1/2 pathway to inhibit inflammation reaction in tolerance to spinal cord I/R injury.
Methods: In the part 1 study, Sprague-Dawley rats were randomly assigned to 4 groups. IPC (P) group animals received IPC by temporary thoracic aortic occlusion (AO) with a 2-F Fogarty arterial embolectomy catheter for 3 min. I/R injury (I/R) group animals were treated with blood withdrawal and temporary AO for 12 min, and shed blood reinfusion at the end of the procedures. (P+I/R) group animals received IPC, followed by 5 min reperfusion, and then I/R procedures for 12 min. Sham (S) group animals received anesthesia and underwent surgical preparation only. Neurological functions were evaluated, and lumbar segments were harvested for histopathological examination. To evaluate the role of autoregulation in IPC, spinal cord blood flow and tissue oxygenation were continuously monitored throughout the procedure duration. In the part 2 study, spinal cord ischemia rats was induced by occluding the thoracic descending aorta with a balloon catheter introduced through a femoral artery, accompanied by concomitant exsanguinations. Rats in the control group were given dimethyl sulfoxide (vehicle) before undergoing spinal cord ischemia/reperfusion injury. In the U0126-treated group, rats were pretreated with an inhibitor of ERK1/2, U0126, to inhibit ERK1/2 phosphorylation. The sham rats underwent aortic catheterization without occlusion. Parameters, including neurologic status, neuronal survival, inflammatory cell infiltration, and interleukin-1β production in the spinal cords, were compared between groups.
Results: The Tarlov scores in the (I/R) group were significantly lower than those in the (S), (P), and (P+I/R) groups on days 1, 3, 5, and 7. The numbers of surviving motor neurons in the (S), (P), and (P+I/R) groups were significantly higher than those in the (I/R) group. The (P) group exhibited higher spinal cord blood flow and tissue oxygenation after reperfusion than the (S) group. The (P+I/R) group exhibited higher spinal cord blood flow and tissue oxygenation within the first 60 min after reperfusion than the (I/R) groups. In the part 2 study, early ERK1/2 phosphorylation was observed after injury in the control group, followed by abundant microglial accumulation in the infarct area and increased interleukin-1β expression. In the U0126 group, U0126 treatment completely blocked ERK1/2 phosphorylation. Microglial activation and spinal cord interleukin-1β levels were significantly reduced. Neuronal survival and functional performance were improved.
Conclusions: IPC ameliorates spinal cord I/R injury in rats, probably mediated by triggering spinal cord autoregulation and improving local spinal cord blood flow and tissue oxygenation. The ERK1/2 pathway may play a noxious role in spinal cord ischemia/reperfusion injury by participating in inflammatory reactions and cytokine production. According to our findings, these concepts may be the new therapeutic targets in patients requiring aortic surgery.

目 錄
論文審定書………………………………………… i
誌謝………………………………………………… ii
中文摘要…………………………………………… iii
英文摘要…………………………………………… v
第 一 章 前言……………………………………… 1
第 二 章…………………………………………… 4
2.1材料與方法…………………………………… 4
2.1.1實驗動物……………………………………… 4
2.1.2實驗設計.……………………………………… 5
2.1.3 脊髓再灌流損傷的實驗模式………………… 5
2.1.4脊髓的缺血前處理的實驗模式………………. 5
2.1.5 脊髓的血流量測量……………………………. 6
2.1.6 脊髓的組織氧氣壓力監測……………………. 6
2.1.7神經學的評估…………………………………... 7
2.1.8脊髓組織切片備置……………………………... 7
2.1.9 組織免疫染色…………………………………... 7
2.1.10計算運動神經元存活量……………………….. 8
2.1.11統計學分析……………………………………... 8
2.2結果………………………………………....... 9
2.2.1血流動力學的指數…………………………….... 9
2.2.2後肢神經學表現.……………………………… 10
2.2.3組織病理檢查報告……………………………. 12
2.2.4脊髓血流監視結果…………………………… 14
2.2.5脊髓的組織氧壓監測結果……………………. 16
2.3討論…………………………………………....... 18
2.4結論…………………………………………....... 25
第 三 章 …………………………………………… 26
3.1材料與方法…………………………………...... 26
3.1.1實驗動物……………………………………….. 26
3.1.2實驗設計.………………………………………… 26
3.1.3脊髓缺血再灌流的實驗模式…………………… 26
3.1.4神經學的評估……………………………………. 27
3.1.5脊髓組織切片備置……………………………... 27
3.1.6組織免疫染色………………………………….... 27
3.1.7組織ERK1/2磷酸化測定…………………….... 27
3.1.8脊髓組織中interlukin-1β的含量測定……….... 28
3.1.9統計分析…………………………………….... 28
3.2結果……………………………………………..... 30
3.2.1動物基本資料……………………………….... 30
3.2.2脊髓ERK1/2磷酸化的研究.………………….. 30
3.2.3神經學評估…………………………………….. 32
3.2.4神經細胞存活結果……………………………... 34
3.2.5微小膠質細胞的活化分析…………………….... 36
3.2.6脊髓組織interlukin-1β的含量測定………….... 38
3.3討論………………………………………………... 40
3.4結論……………………………………………… 42
第 四 章 總 結…………………………………… 43
參考文獻……………………………………………………… 44
附錄…………………………………………………… 53

圖　次
圖一 後肢神經學表現…………………………………… 11
圖二 脊髓組織病理檢查………………………………… 13
圖三 脊髓血流監視結果………………………………… 15
圖四 脊髓的組織氧壓監測結果………………………… 17
圖五 脊髓ERK1/2磷酸化的研究……………………… 31
圖六 後肢神經學表現…………………………………… 33
圖七 脊髓神經細胞存活結果…………………………… 35
圖八 微小膠質細胞的活化分析………………………… 37
圖九 脊髓組織interlukin-1β的含量測定……………… 39

表 次
表一 血流動力學的指數………………………………… 9

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