輸液治療部分恢復出血性休克加乘誘發糖尿病大鼠造成之心肌傷害機轉探討; Resuscitation partially restores the synergistic cardiac damage induced by hemorrhagic shock in diabetic rats

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題名:	輸液治療部分恢復出血性休克加乘誘發糖尿病大鼠造成之心肌傷害機轉探討;Resuscitation partially restores the synergistic cardiac damage induced by hemorrhagic shock in diabetic rats
作者:	林冠合;Kuan-Ho Lin
貢獻者:	中國醫藥大學：臨床醫學研究所碩士班
關鍵詞:	糖尿病;心臟;外傷;出血性休克;心肌細胞傷害;凋亡;存活;diabetes;heart;trauma;hemorrhagic shock;myocardial cell damage;apoptosis;survival
日期:	2009-07-15
上傳時間:	2009-08-12 14:23:33 (UTC+8)
摘要:	糖尿病患者之主要臨床症狀除了血糖過高外，亦常伴隨血脂異常的發生，增加併發心血管疾病的危險性外，外傷引起的壓力更是糖尿病病情的促進因子。外傷一直是台灣地區四十歲以下民眾的第一殺手。外傷死亡早期主要原因包括頭部外傷與出血性休克，晚期則為器官衰竭。儘管過去一、二十年間，許多的臨床與基礎之研究，仍然無法針對多重器官衰竭作有效的改善，其死亡率仍高達40~50%。而當病患本身有糖尿病及外傷兩種因素時，體內更會大量產生如氧化壓力(ex: reactive oxygen species, ROS)、被修飾的脂蛋白、血流的壓迫等而造成細胞損傷。同時會激起各種生理反應，其中細胞激素(cytokine)的釋放，會造成過度的發炎反應，使細胞與組織受損進而引起併發症的發生，但出血性外傷是否造成心肌損傷及二者是否因此加乘傷害患者心肌細胞組織及其分子訊息機轉，且使用輸液治療後是否能完全回復，其答案及機制均有待進一步探討。本研究乃藉助鏈氮黴素(Streptozotocin, STZ) 注射65mg/ml/kg誘發6~8週齡大白鼠，一週後測血糖>200mg/dl則視為高血糖大鼠，再施以出血性休克一小時模式並進行有無輸液治療處理，來加以探討糖尿病伴隨出血性休克在有無輸液治療後其心肌細胞損害的差異。實驗將大白鼠的左心室游離，並採用西方墨點法，及組織染色切片分析。實驗結果顯示糖尿病現象及出血性休克均造成胚胎基因IGFII表現增加，造成IGFIIR pathway活化, 並經Gαq 、PKCα進一步活化calcineurin（Ca2+-sensitive phosphatase），並 dephsophoylated p-Bad使其變成Bad，Bad因與粒線體膜結合，促使粒線體膜上電子傳遞鏈遭到破壞，而造成粒線體膜電位不穩定，進而使Cytochrome c由粒線體內釋出並活化下游Caspase 9及3；引發DNA斷裂並使得心肌細胞走向凋亡。但所有現象均在輸液治療後有部分回復的現象。同時輸液補充並進一步促進survival 路徑相關蛋白，如PI-3k， p-Akt 及p-Bad的表現。對survival pathway的壓制，以糖尿病組(DM)影響大於出血性休克組(HS)；且在兩個因素結合的組別更具有加乘性的傷害。而對apoptosis pathway的促進作用則是出血性休克組影響大於糖尿病組(DM)；而糖尿病合併出血性休克組(DM+HS)更加乘性促進；但在輸液治療的組別(DM+HS+R)，則明顯具有抑制其傷害並且呈現部分恢復的結果。綜合所有證據顯示，糖尿病大白鼠伴隨大量出血性休克後確實造成心肌細胞加乘性的傷害，並經加乘活化IGF-II pathway與粒線體障礙誘發心肌細胞走向凋亡，惟輸液治療後有減緩且部分恢復的現象，但終究無法完全使其恢復。 The major clinical symptom of diabetic is excessively high blood glucose level, followed with the increase of abnormal blood lipid, and the risk of cardiovascular disease. In Taiwan, the incidence of diabetes is increasing. Today, trauma has the highest mortality rate in the population below 40 years old of Taiwan, and the major death causes of trauma are head injury and hemorrhagic shock in early time, organ failure in later period. Though during past ten to twenty years had operated much clinical and basic research, it was still less effective improvement, the mortality rate still reached as high as 40~50%. When patient has diabetes and/or trauma factors, it will induce the oxidized pressure (ex: reactive oxygen species, ROS), decorated lipoprotein, blood stream oppression, and create the cell damage. In addition, the cytokine release will lead the excessive inflammation, it will cause the cells and organizations injury and then complications occurred. However, if the synergistic injury effects of these two factors will occur in myocardial cell, the exactly molecular mechanisms, and if the resuscitation treatment recover the damage, were needed to be further revealed. This research used the diabetic rats induced by Streptozotocin, (STZ, 65mg/ml/kg). Then, the diabetic rats treated with or without hemorrhagic shock, and resuscitation was applied to the diabetic plus hemorrhagic shock rats. We aim to investigate if the myocardial cell injury in diabetes rat will be enhanced by trauma-induced hemorrhagic shock, and whether resuscitation will rescue the damage effect. The excised left ventricles from rats was applied to Western blotting and histological analysis. Result showed that diabetics and hemorrhagic shock cause the embryonic gene IGFII expression increase, and may pass through IGFIIR pathway, activating Gαq and PKCα, further activate calcineurin (Ca2+-sensitive phosphatase), and dephsophoylated p-Bad into Bad. Then, Bad binds to the mitochondrium membrane, induces the imbalance of the energy producing electron transferring chain on the mitochondrion membrane, causes the mitochondrion membrane potential unstable, and then causes Cytochrome c releasing from the mitochondrion and activates downstream Caspase 9、3. The caspases cause DNA fragmentation and lead the myocardial cell toward apoptosis. However, all phenomena have partially recover after resuscitation treatment. Resuscitation even further promotes the cardiac survival pathway related protein, PI-3k, p-Akt and p-Bad activation. The combination of diabetes mellitus and hemorrhagic shock contribute to synergistically damage in cardiac apoptosis. Diabetes mellitus has the dominant negative effect in survival pathway, while hemorrhagic shock has the dominant positive influence in apoptosis pathway. Treatment of resuscitation provides partially therapeutic effect on damage and improve the survival pathway from diabetes mellitus combined with hemorrhagic shock. This research could provide some useful information to patients has diabetes mellitus and undergone hemorrhagic shock and resuscitation treatment. All evidences demonstrated the diabetic rat under trauma-induced hemorrhagic shock, synergistically causes the myocardial cell damage. Resuscitation partially restores the myocardial cell damage.
顯示於類別:	[臨床醫學研究所] 博碩士論文

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