本實驗的首要目的為研究大鼠單側頸部脊髓挫傷對於橫膈與肋間肌的活性影響。大鼠在頸部第3節左側進行挫傷，麻醉動物在損傷當下以及損傷後3天、2與8週測量雙側橫膈與肋間肌肌電圖活性。第一個目的實驗結果表示，單側頸部挫傷會導致雙側橫膈及肋間肌的吸氣放電活性立即降低。挫傷後3天-8週，麻醉損傷動物的潮氣容積皆顯著低於未損傷動物，損傷動物的損傷對側橫膈肌電圖放電強度在3天後相較未損傷動物是增強的。當肌電圖數據使用低氧刺激(12-13 % O2，3-4 % CO2)期間所誘發的最大吸氣活性進行標準化，損傷後3天、2週損傷側橫膈的數值是顯著高於未損傷動物。低氧誘發損傷側橫膈活性增強的反應在損傷後2週減弱但在8週後恢復。雙側橫膈放電強度在損傷後8週已經與未損傷動物沒有差異。肋間肌肌電圖活性在損傷後3天-8週並沒有受到中段頸部挫傷影響。甲酚紫組織染色顯示挫傷顯著損害損傷側白質與灰質，8週後有明顯的空腔產生，損傷些微地擴大至未損傷側。第二個目的為評估急性間歇低氧刺激是否能在挫傷後不同階段恢復呼吸功能。清醒動物在損傷後3天、2與8週進行全體腔呼吸描記，記錄中度急性間歇低氧刺激前後的反應。實驗結果表示，挫傷後3天-8週，清醒動物的潮氣容積皆是顯著低於未損傷動物，但發現呼吸頻率在3天、2週是顯著提升。損傷及未損傷動物在挫傷後3天、2週、8週於急性低氧刺激期間的分鐘換氣量有顯著上升，但損傷動物在3天、2週的低氧反應是顯著低於未損傷動物。在10次急性間歇低氧(5分鐘10 % O2, 4 % CO2, 86 % N2間隔5分鐘常氧)刺激後的60分鐘內，損傷後3個時間點的潮氣容積都有顯著的增強。逆向神經追蹤劑標定單側頸部挫傷後的橫膈運動神經元顯示損傷動物損傷側橫膈運動神經元數量顯著少於損傷對側以及未損傷動物。這些結果表示中段頸部脊髓挫傷導致損傷對側橫膈活性代償性增加，損傷側橫膈則使用較大的力維持正常呼吸，肋間肌活性可能有助於脊髓損傷後穩定呼吸功能。頸部脊髓挫傷的動物仍保有呼吸神經可塑性，急性間歇低氧刺激可誘發神經可塑性，可用於治療頸部脊髓損傷急性期至慢性期的呼吸功能障礙。

The first purpose of present study was designed to investigate the diaphragm and intercostal muscle activity following unilateral mid-cervical spinal cord contusion in rats. Electromyogram (EMG) activity of the bilateral diaphragm and T2 intercostal muscle was measured in anesthetized rats at immediate injury state, 3 days, 2 and 8 weeks post-injury. The results demonstrated that unilateral mid-cervical contusion caused an immediate reduction in inspiratory bursting in the bilateral diaphragm and intercostal muscles. From 3 days to 8 weeks post-contusion, the contused animals exhibited significant lower tidal volume than uninjured animals. The burst amplitude of the contralateral diaphragm EMG was augmented in contused animals at 3 days post-injury. When data were normalized by the maximal response during hypoxia (12-13 % O2, 3-4 % CO2), the ipsilateral diaphragm EMG of contused animals was greater than that of uninjured animals at 3 days and 2 weeks. Moreover, hypoxia-induced increases in ipsilateral diaphragm EMG activity were blunted in contused animals at 2 weeks but recovered at 8 weeks post-injury. Bilateral diaphragm EMG activity in contused animals was comparable to uninjured animals at 8 weeks post-injury. Intercostal muscle activity was not substantially changed by mid-cervical spinal cord contusion from 3 days to 8 weeks post-contusion. The histological results demonstrated a significant disruption of both grey and white matter was observed at lesion epicenter. The second aim was to investigate whether mild acute intermittent hypoxia (AIH:10 episodes of 5 min 10 % O2, 4 % CO2, with 5 min of normoxia intervals) can induce respiratory recovery at different injury state following mid-cervical spinal contusion. The ventilatory response of AIH of conscious rats was measured by the whole body plethysmography at 3 day, 2 week and 8 weeks post injury. The results demonstrated that tidal volume was decreased at the three time points, and frequency was increased in contused animals compared with uninjured animals at 3 day, 2 week. Acute hypoxia induced significant increases in the minute ventilation in both groups; however, contused animals had a weaker response at 3 day and 2 week post injury. Tidal volume of contused animals could be significantly enhanced within 60 min post-AIH at three time points. The monosynapic retrograde tracer data showed that the number of phrenic motoeurons in the contused animals was significantly reduced. These results suggest that mid-cervical spinal contusion induces a compensatory increase in contralateral diaphragmatic activity and greater utilization of a percentage of maximal inspiratory activity in the ipsilateral diaphragm. The maintenance of intercostal muscle activity may enable the animal to sustain essential breathing capacity following cervical spinal cord injury. Cervical contused animals can retain the capacity to express respiratory neuroplasticity, and AIH may be a potential neurorehabilitative therapy to restore the breathing function from the acute to chronic injury state.

論文審定書....................................................................................................i
中文摘要 ......................................................................................................ii
英文摘要 .....................................................................................................iii
第一章 前言 .................................................................................................1
1-1脊髓損傷..............................................................................................1
1-2呼吸功能的基本神經管制.....................................................................2
1-3頸部脊髓損傷對於呼吸功能的影響.......................................................3
1-4低氧誘發的呼吸神經可塑性.................................................................5
1-5呼吸相關神經調控物質........................................................................6
1-6目的......................................................................................................7
第二章 材料與方法 ......................................................................................9
2-1實驗動物與動物組別............................................................................9
2-2頸部脊髓挫傷手術................................................................................9
2-3麻醉動物呼吸氣流、呼吸末二氧化碳、心跳與血壓測量......................10
2-4血液參數測量......................................................................................11
2-5橫膈與肋間肌的肌電圖測量................................................................11
2-6麻醉動物生理學實驗流程...................................................................12
2-7清醒動物呼吸參數測量.......................................................................12
2-8組織學.................................................................................................13
2-9逆向神經追蹤劑標定橫膈運動神經元..................................................14
2-10數據分析與統計 ................................................................................15
第三章 結果..................................................................................................17
3-1單側頸部挫傷後對於雙側橫膈、肋間肌立即性的活性影響..................17
3-2麻醉動物的呼吸型態、呼氣末二氧化碳、心跳與血壓..........................17
3-3呼吸型態、呼氣末二氧化碳、心跳血壓對於低氧刺激的變化...............18
3-4麻醉動物的橫膈與肋間肌的肌電圖.......................................................19
3-5橫膈與肋間肌對於低氧刺激期間的肌電圖變化.....................................20
3-6甲酚紫組織學染色.................................................................................21
3-7免疫螢光染色.........................................................................................21
3-8清醒動物的呼吸型態..............................................................................22
3-9清醒動物的呼吸型態對於間歇低氧期間的變化.......................................22
3-10清醒動物的呼吸型態在間歇低氧刺激後的長期增益效應......................23
3-11逆向神經追蹤劑標定橫膈運動神經元...................................................24
第四章 討論....................................................................................................25
4-1方法討論.................................................................................................26
4-2中段頸部挫傷對呼吸型態的影響.............................................................26
4-3中段頸部挫傷對於橫膈與肋間肌活性的影響............................................27
4-4中段頸部挫傷對於血清素分佈影響..........................................................29
4-5間歇低氧刺激與長期增益效應.................................................................29
4-6生理意義..................................................................................................31
第五章 圖與說明..............................................................................................32
第六章 表與說明..............................................................................................54
參考文獻..........................................................................................................59

圖次
圖1 橫膈與肋間肌的神經管制示意圖....................................................32
圖2 撞擊裝置............................................................................................33
圖3 第二部分麻醉動物測量示意圖........................................................34
圖4 呼吸參數測量....................................................................................35
圖5 脊髓組織計算示意圖........................................................................36
圖6 頸部脊髓單側挫傷後橫膈與肋間肌立即性的反應........................37
圖7 損傷後3天-8週雙側橫膈、肋間肌肌電圖活性範例圖................38
圖8 麻醉動物的呼吸型態、呼氣末二氧化碳..........................................41
圖9 麻醉動物在低氧刺激期間的血壓、心跳..........................................42
圖10麻醉動物在低氧刺激期間的呼吸型態...........................................43
圖11麻醉動物橫膈、肋間肌的吸氣放電強度.......................................44
圖12麻醉動物在低氧刺激期間橫膈、肋間肌的反應...........................45
圖13第二部分甲酚紫組織學染色...........................................................46
圖14第二部分頸部脊髓免疫組織螢光染色...........................................47
圖15第二部分胸段脊髓免疫組織螢光染色...........................................48
圖16清醒動物的呼吸氣流範例圖...........................................................49
圖17清醒動物的呼吸型態.......................................................................50
圖18清醒動物的間歇低氧的反應...........................................................51
圖19清醒動物間歇低氧後的長期增益效應...........................................52
圖20第三部分逆向神經追蹤劑標定橫膈運動神經元...........................53

 
表次
表1 縮寫表................................................................................................54
表2 麻醉動物體重....................................................................................55
表3 清醒動物體重....................................................................................55
表4 麻醉動物受到低氧刺激後誘發的呼吸增強反應............................55
表5 麻醉動物呼氣末二氧化碳於低氧刺激的反應................................56
表6 麻醉動物PaO2與PaCO2在基礎值與低氧刺激反應…..................57
表7 清醒動物時間對照組之呼吸型態....................................................58

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