本研究分為兩個主要的部份，第一部份是有關於脊髓缺血再灌流傷害後傷害之嚴重程度與細胞死亡機制之間的關係以及神經保護之探討。胸腰椎脊髓之血液供應主要是來自於胸腹主動脈。因脊髓缺血而導致下肢癱瘓是胸腹主動脈手術的嚴重併發症。先前的研究指出中樞神經系統之缺血再灌流傷害會引起兩種不同形態之細胞死亡，即細胞壞死和細胞凋亡。也有研究暗示傷害之嚴重程度可能會影響到細胞死亡之機制。在第一部份的研究中，我們將大白鼠之胸主動脈阻塞造成脊髓之缺血再灌流傷害，並且藉由是否同時抽血引發缺血性低血壓，建立了一個可以控制傷害嚴重程度之脊髓缺血再灌流的動物模型。術中頸動脈血壓及脊髓血流量監測顯示，胸主動脈阻塞在正常血壓組與低血壓組之大白鼠都會造成大幅的頸動脈血壓上升及脊髓血流量降低。然而，低血壓組在胸主動脈阻塞期間之脊髓血流量降得更低，再灌流後脊髓血流量回升之速度較緩慢，而且後肢之運動功能受損程度也較為嚴重。腰椎段脊髓表現出嚴重之梗塞、明顯之細胞壞死、及缺乏細胞凋亡之現象。相反地，正常血壓組在受到相同時間之脊髓缺血再灌流傷害後，脊髓組織傷害及後肢之運動功能受損程度都較為輕微，但是細胞凋亡之現象及caspase-3之活性卻較為旺盛及持續。而脊髓前角中之運動神經細胞較少發生細胞凋亡之現象可能是正常血壓組神經功能受損較輕微的主要原因。我們的研究發現缺血再灌流傷害之嚴重程度對受傷脊髓之病理變化及細胞死亡之機制有相當程度之影響。我們的研究結果也暗示，傷害的嚴重程度及傷害後之時間點是在從事治療時必須要考慮之重要因素。
由於細胞壞死及細胞凋亡是脊髓缺血再灌流傷害後會引發細胞死亡之兩種主要機制，我們因而假設將NMDA接受器抑制劑MK-801及蛋白質合成抑制劑cycloheximide併用可能在脊髓缺血再灌流傷害之治療上有加成之效果。在第二部份的研究中，我們仍然將大白鼠之胸主動脈阻塞並同時減少血液容積量以造成脊髓之缺血，將抽出之血液注回以引起再灌流傷害。然後我們將大白鼠分為四個實驗組，分別接受載體、MK-801、cycloheximide、或MK-801與cycloheximide合併之治療。研究結果顯示，MK-801組及合併治療組後肢運動功能之恢復優於控制組及cycloheximide組。三個治療組在第七天之神經細胞存活率顯著優於控制組。與控制組相比，cycloheximide組與合併治療組之脊髓切面上之凋亡細胞總數有顯著之減少。而MK-801組則維持不變。這些結果顯示同時將與NMDA接受器有關之細胞毒性及與caspase 有關之細胞凋亡抑制可能在脊髓缺血再灌流傷害之治療上有相當之潛力。
Mitogen-activated protein kinases (MAPK) 包括了c-Jun N-terminal kinases (JNK)、 p38及extracellular signal-regulated kinases (ERK)，在細胞面臨壓力時訊息的傳遞和細胞反應的整合中扮演了重要的角色。雖然一般的看法認為JNK和 p38與細胞的死亡及退化有關，而ERK則是與細胞的分裂及存活有關，爭論卻依然存在。尤其是關於ERK訊息傳遞路徑在中樞神經系統之缺血再灌流傷害中所扮演之角色，文獻上有完全相反的報告，因此極待釐清。基於這樣的爭議，在第三部份的實驗中，我們檢測脊髓缺血再灌流傷害後ERK1/2之變化，以及抑制使ERK1/2磷酸化之分子MEK之效果。實驗結果顯示，缺血再灌流傷害在脊髓內引發立即性的ERK1/2磷酸化，而此磷酸化可被MEK之抑制劑U0126所抑制。
控制組的神經缺損恢復較差、脊髓組織破壞較嚴重、細胞凋亡之現象較明顯、神經細胞存活率也較低。相反的，U0126治療組後肢運動功能之進步較明顯、脊髓組織破壞較輕微、細胞凋亡之現象較少、神經細胞存活率也較高。此外，U0126的給予也顯著提高了nuclear factor-κB (NF-κB)之活化與cellular inhibitor of apoptosis protein 2 (c-IAP2)之表現。這些發現暗示著抑制ERK1/2所造成的神經保護效果可能是經由NF-κB-c-IAP2這條路徑所致。MEK-ERK訊息傳遞路徑過度活化在我們的實驗模型中所扮演之角色似乎是弊多於利。能夠將此一路徑阻斷之策略或許在脊髓缺血再灌流傷害的治療上具有相當之潛力。
本研究之第二部份是有關於背側脊椎手術與脊柱側肌肉傷害之關係，與避免此類傷害方法之探討。在執行背側脊椎手術時經常須要將脊柱側肌肉剝離並用力撐開，此舉可能會對此肌肉造成結構及功能上之傷害。術後脊柱側肌肉中立即發生之病理變化不僅會造成嚴重的疼痛，也會延遲病患下床活動的時間。長期的不良結果還包括了慢性背痛及背部肌肉無力。諷刺的是，雖然脊柱側肌肉的傷害是背側脊椎手術常見的併發症，它卻是如此地被忽略。文獻中有限的報告指出外科手術對脊柱側肌肉之傷害包括了物理性與缺血性之傷害。我們因而假設手術中剝離與撐開的動作會對脊柱側肌肉造成氧化壓力。同時，我們也假設此氧化壓力會在受創肌肉中引發某種自我保護之機制。此研究之第一部份涉及一人體試驗，目的在於評估手術中撐開下人體脊柱側肌肉內氧化壓力所扮演之角色與其和由heat shock protein (HSP70)主導的壓力反應機制之間的關係。
試驗對象是一群因患有腰椎滑脫必須接受背側腰椎融合、固定及減壓手術之病患。手術中在脊柱側肌肉撐開前、撐開中及撐開後固定時間點作多裂肌之切片。我們分別檢測肌肉檢體中之HSP70和malondialdehyde (MDA)的量。結果顯示手術中的肌肉撐開會使多裂肌細胞中之HSP70和malondialdehyde (MDA)的量顯著上升。肌肉中HSP70的表現在撐開後約1.5小時後開始下降，而MDA的量卻一直到肌肉撐開器放鬆後都還維持上升之狀態。病理組織學及免疫組織染色之證據顯示撐開晚期HSP70合成之減少是肌肉嚴重受損之結果。
這些實驗結果在細胞及分子層面指出了手術中將脊柱側肌肉撐開對該肌肉之害處，以及氧化壓力之重要性。這些結果也暗示能夠降低脊柱側肌肉中氧化壓力之措施或許可以減少手術對脊柱側肌肉之傷害。
基於上述之發現，也由於文獻中指出發炎反應是發生於受到手術傷害之脊柱側肌肉中主要的病理變化，我們於是進一步檢測兩個與發炎反應有關之重要介質，即cyclooxygenase (COX)-2 和nuclear factor (NF)-κB，在手術所引起之脊柱側肌肉傷害中所扮演之角色。
首先我們建立了一個摹擬人體背側脊椎手術之大白鼠模型。控制組大白鼠先接受背側脊柱側肌肉之剝離及撐開。脊柱側肌肉撐開前、撐開中及撐開後固定時間點作肌肉之切片。經由對這些肌肉檢體之分析，我們分別檢測NF-κB之活化和COX-2之表現的時間順序。發炎反應之嚴重程度則由組織中病理變化及myeloperoxidase (MPO)的量來評估。另一組大白鼠接受同樣之手術步驟，但給予pyrrolidine dithiolcarbamate (PDTC)以抑制NF-κB之活化。實驗結果顯示在控制組中，肌肉撐開會使脊柱側肌肉細胞中之NF-κB/DNA之結合能力在撐開早期就上升，並在整個撐開過程中持續。而COX-2之表現要到術後一天時才能檢測得到，並且在第三天時達到高峰。COX-2表現之時間與病理切片及MPO量所透露出的發炎嚴重度相當一致。術後七天時肌肉切片顯示廣泛的肌肉細胞喪失及纖維組織增生的現象。而術前給予PDTC有效地抑制NF-κB之活化，並大幅降低了COX-2的表現和肌肉中的發炎。肌肉組織纖維化的情形也顯著地減少。
這些實驗結果顯示由NF-κB調控之COX-2表現及發炎反應在手術所引起之脊柱側肌肉之傷害機制中扮演了重要之角色。能夠抑制NF-κB活化之治療策略或許可應用於保護脊柱側肌肉免於此類傷害。

Abstract
The first part of this research was focused on the relationship between injury severity and cell death mechanisms after spinal cord ischemia-reperfusion injury. The major blood supply to the thoracolumbar spinal cord comes from the segmental arteries originating from the thoracoabdominal aorta. Paraplegia cause by spinal cord ischemia is a devastating complication of thoracoabdominal aortic surgery. Previous studies indicated that ischemia-reperfusion injury of the central nervous system causes two distinct types of cell death, necrosis and apoptosis. It was also implicated that the intensity of injury can somehow affect the cell death mechanisms. In the first series of our experiments, by occluding the descending thoracic aorta with or without simultaneously inducing hypovolemic hypotension in rats, we established a model of experimental spinal cord ischemia-reperfusion (SCIR) in which the injury severity can be controlled. Recordings of carotid blood pressure (CBP) and spinal cord blood flow (SCBF) showed that aortic occlusion induced dramatic CBP elevation but SCBF drop in both the normotensive (NT) and hypotensive (HT) groups. However, the HT group demonstrated significantly lower SCBF during aortic occlusion, and much slower elevation of SCBF after reperfusion, and extremely poor neurological performance. Spinal cord lesions were characterized by infarction associated with extensive necrotic cell death, but little apoptosis and caspase-3 activity. In contrast, in the NT group, SCIR resulted in minor tissue destruction associated with persistently abundant apoptosis, augmented caspase-3 activity, and favorable functional outcome. The relative sparing of motoneurons in the ventral horns from apoptosis might have accounted for the minor functional impairment in the NT group. The severity of ischemia-reperfusion (I/R) injury was found to have substantial impact on the histopathological changes and cell death mechanisms, which correlated with neurological performance. These findings implicate that injury severity and duration after injury are two critical factors to be considered in therapeutic intervention.
Based on the knowledge that bPrevious studies have implicated both excitotoxicity and apoptosis are involved in the pathogenesis of SCIR injury, we proposedtested the possibility that the N-methyl-D-aspartate (NMDA) receptor antagonist (dizocilpine maleate: (MK801) and the protein synthesis inhibitor (cycloheximide) would produce a synergic effect in the treatment of SCIR injury. In the second series of experiments, I/R iSpinal cord ischemia-reperfusion injury was induced by a thoracic aortic occlusion and blood volume reduction, followed by reperfusion and volume restoration. ischemia-reperfusion Rats were treated with vehicle, MK801, cycloheximide, or combination of MK801 and cycloheximide in combination. The MK801 and combined therapy group got a better recovery of hHind limb motor function recovery was better in the MK801 and combined-therapy groups than in the control and cycloheximide groups. On the 7th day after ischemia-reperfusion injury, all three treated groups showed significantly higher neuronal survival rates (NSR) than that of the control group. Among the three treated groups, the combined-treatment group showed the highest NSR. In addition, the Ttherapeutic effect of the combined-treatment group (27.4% increase of NSR) iwas better than the anticipated by the addition of MK801 and cycloheximide based on NSR data group. The number of apoptotic cells of was significantly reduced in the cycloheximide group and the combined-treatment group, as compared to that of the control group. It was unchanged in the MK-801 group. These results suggest that combined treatments directed at blocking both NMDA receptor-mediated excitotoxic necrosis and caspase-mediated apoptosis might have synergic therapeutic potential in reducing SCIR injury.
Mitogen-activated protein kinases (MAPKs) including c-Jun N-terminal kinases (JNK), p38, and extracellular signal-regulated kinases (ERK), play important roles in the transduction of stressful signals and the integration of cellular responses. Although it has been generally held that the JNK and p38 pathways are related to cell death and degeneration, while the ERK pathway, cell proliferation and survival, controversy still exists. The roles of the ERK pathway in I/R injury of the CNS, in particular, remain to be clarified, because contradictory data have been reported by different investigators. Given this controversy, in the third series of experiments, we examined in injured spinal cords the temporal and spatial profiles of ERK1/2 activation following SCIR, and the effects of inhibiting the kinase that phosphorylates ERK1/2, MEK. The results showed that I/R injury induced an immediate phosphorylation of ERK1/2 in the spinal cord, which was alleviated by a MEK inhibitor, U0126. The control group was characterized by poorer neurological outcome, more severe tissue destruction, pronounced apoptosis, and lower neuronal survival. In contrast, the U0126-treated group demonstrated more apparent improvement of hind limb motor function, less tissue destruction, lack of apoptosis, and higher neuronal survival. In addition, administration of U0126 also significantly increased the activation of nuclear factor-κB (NF-κB) and the expression of cellular inhibitor of apoptosis protein 2 (c-IAP2). These findings implicate that the mechanisms underlying the neuroprotection afforded by ERK1/2 inhibition may be through the NF-κB-c-IAP2 axis. The activation of the MEK-ERK signaling pathway appeared to be harmful in SCIR injury. Strategies aimed at blocking this pathway may bear potential therapeutic benefits in the treatment of SCIR injury.
The second part of the research was focused on the pathophysiology of surgery-associated paraspinal muscle injury and measures to protect surgically violated paraspinal muscles. The wide dissection and forceful retraction of paraspinal muscles which are often required for posterior spinal sugery may severely jeopardize the muscles structurally and functionally. Immediate posteoperative pathological changes in the surgically violated paraspinal muscles may cause severe pain and a delay of patient ambulation. Long-term sequelae of surgical injury of paraspinal muscles include chronic back pain and impaired back muscle strength. Ironically, being a common complication of posterior spinal surgery, paraspinal muscle injury is so often neglected. Limited previous data indicate that the underlying pathophysiology of muscle damage involve both mechanical and ischemic mechanisms. We hypothesized that surgical dissection and retraction may produce oxidative stress within the paraspinal muscles. Meanwhile, we also proposed that the oxidative stress may trigger certain protective mechanisms within the insulted muscles. The first part of our study was a human study conducted to assess the significance of oxidative stress, and the relationship between it and the stress response mediated by heat shock protein 70 (HSP70) induction within paraspinal muscles under intraoperative retraction.
A group of patients with lumbar spondylolisthesis treated with posterolateral lumbar spinal fusion, pedicle fixation and laminectomy were enrolled. Multifidus muscle specimens were harvested intraoperatively before, at designated time points during, and after surgical retraction. Muscle samples were analyzed for HSP70 and malondialdehyde (MDA) levels. Both HSP70 expression and MDA production within multifidus muscle cells were increased significantly by retraction. HSP70 expression then dropped after a peak at 1.5 hr of retraction, whereas MDA levels remained elevated even after release of retractors for reperfusion of the muscles. Histopathological and immunohistochemical evidence indicated that the decline of HSP70 synthesis within muscle cells after prolonged retraction was the result of severe muscle damage.
These results highlighted the noxious impact of intraoperative retraction on human paraspinal muscles, and the significance of oxidative stress at the cellular and molecular levels. It is also implicated that intraoperative maneuvers aimed at reducing the oxidative stress within the paraspinal muscles may help attenuating surgery-associated paraspinal muscle damage.
Given the findings of the first part of our study, and the knowledge that inflammation is a major postoperative pathological finding in surgically injured paraspinal muscles, we proceeded to examine the roles of two important inflammatory mediators, cyclooxygenase (COX)-2 and nuclear factor (NF)-κB, in the pathogenesis of retraction-associated paraspinal muscle injury.
A rat model of paraspinal muscle dissection and retraction that mimicks the conditions in human posterior spinal surgery was established. In the control group, paraspinal muscles were dissected from the spine through a dorsal incision, and then laterally retracted. Paraspinal muscle specimens were harvested before, and at designated time points during and after persistent retraction. The time course of NF-κB activation as well as the expression of COX-2 were examined. Severity of inflammation was evaluated based on histopathology and myeloperoxidase (MPO) activity. NF-κB activation was inhibited by the administration of pyrrolidine dithiolcarbamate (PDTC) in the PDTC-treated group. In the control group, retraction induced an early increase of NF-κB/DNA binding activity in paraspinal muscle cells, which persited throughout the whole course of retraction. COX-2 expression was not detectable until 1 day after surgery, and reached a peak at 3 days. The time course of COX-2 expression correlated with that of inflammatory pathology and MPO activity. Extensive muscle fiber loss and collagen fiber replacement were observed at 7 days after surgery. Pretreatment with PDTC inhibited intraoperative NF-κB activation and greatly downregulated postoperative COX-2 expression and inflammation in the muscles. Fibrosis following inflammation was also significantly abolished by PDTC administration.
These findings indicate that NF-κB-regulated COX-2 expression and inflammation play an important role in the pathogenesis of surgery-associated paraspinal muscle injury. Therapeutic strategies involving NF-κB inhibition may be applicable to the prevention of such injury.

中文摘要 ……………………………………………………………………………..1
Abstract ……………………………………………………………………………….5

Chapter 1 Injury Severity and Cell Death Mechanisms: Effects of Concomitant Hypovolemic Hypotension on Spinal Cord Ischemia-Reperfusion in Rats
1.1 Introduction ……………………………………………………………………..11
1.2 Hypotheses and Research Objectives ……………………………………………15
1.3 Materials and Methods …………………………………………………………..16
1.4 Results …………………………………………………………………………...22
Table 1.1 ……………………………………………………………………………..26
1.5 Discussion ……………………………………………………………………….37
1.6 Conclusion ………………………………………………………………………42

Chapter 2 Inhibition of Phosphorylation of Extracellular Signal-Regulated Kinases (ERK1/ERK2) Provides Neuroprotection after Spinal Cord
2.1 Introduction ………………………………………………………...……………43
2.2 Materials and Methods ………………………………………………...………...47
2.3 Results ……………………………………………………...……………………51
2.4 Discussion …………………………………………...…………………………..64
2.5 Conclusions …………………………………..……………………….…………66

Chapter 3 Oxidative Stress and Heat Shock Protein Response within Human Paraspinal Muscles during Retraction
3.1 Introduction ……………………………………………..……………………… 67
3.2 Materials and Methods ………………………………..…………………………70
3.3 Results ………………………………………………..………………………… 75
Table 3.1 ……………………………………………………………………………..77
3.4 Discussion …………………………………………….…………………………82
3.5 Conclusions ……………………………………..……………………………….84

References …………………………………………………..……………………….87

Chapter 4 Nuclear Factor-κB-Regulated Cyclooxygenase-2 Expression in Surgery-Associated Paraspinal Muscle Injury in Rats
4.1 Introduction ……………………………………………………………………..88
4.2 Materials and Methods ………………………………………………………….91
4.3 Results …………………………………………………………………………...97
4.4 Discussion ……………………………………………………………………...106
4.5 Conclusion ……………………………………………………………………..110

Chapter 5 Directions of Future Research
5.1 On the Autoregulation of Spinal Cord Blood Flow ……………………………111
5.2 On Signal Transduction Pathways …..…………………………………………113
5.3 On Surgery-Associated Paraspinal Muscle Injury ………….………………….114

References ………………………………………………………………………….116

Acknowledgment …………………………………………………………………..135

Publications Related to this Thesis ………………………………………………....136

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