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研究生:吳文田
研究生(外文):Wen-Tien Wu
論文名稱:紅血球生成素對於失血性休克及內毒素血症引發的器官損傷之影響
論文名稱(外文):Effects of Erythropoietin on Organ Damage Induced by Hemorrhagic Shock and Endotoxemia
指導教授:林念璁林念璁引用關係徐邦治徐邦治引用關係
指導教授(外文):Nien-Tsung LinBang-Gee Hsu
學位類別:博士
校院名稱:慈濟大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:132
中文關鍵詞:失血性休克內毒素休克紅血球生成素發炎前細胞激素
外文關鍵詞:Hemorrhagic shockEndotoxin shockErythropoietinPro-inflammatory Cytokines
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失血性休克(Hemorrhagic shock;HS)會導致血液動力學的不穩定,減少氧氣的運送及組織灌流,引起細胞缺氧及多重器官衰竭。在分子層面,轉錄因子Nuclear factor-κB (NF-κB) 被活化,參與細胞凋亡及發炎的一系列反應,大量產生發炎前細胞激素,如Tumor necrosis factor-α (TNF-α)、Interleukin-6(IL-6) 及Interleukin-1β(IL-1β),會導致多重器官功能障礙及死亡。革蘭氏陰性菌感染時,其細胞壁的內毒素或脂質多醣體(Lipopolysaccharide;LPS)也會引起發炎前細胞激素的產生,嚴重時,造成多重器官失能併死亡。紅血球生成素(Erythropoietin; EPO)已被證實可以和多種非造血組織中的接受器作用而引發一系列非典型的細胞保護作用。本研究分為兩大主軸,分別以清醒大鼠模式,探討(一)EPO對於HS引發的器官損傷之影響,以及(二) EPO對於內毒素血症引發的器官損傷之影響。
在第一部分的HS研究方面,大鼠在失血前先經由股靜脈給予EPO 300單位/公斤,接著自股動脈抽出60%的血液,進行HS,失血時間為30分鐘。自失血開始,連續記錄大鼠的平均動脈壓(Mean arterial pressure;MAP)及心率(Heart rate;HR)18小時。在失血前30分鐘及失血後第0、1、3、6、9、12及18小時分別檢測血液及生化指標,包括血色素、麩草醋酸轉氨酶(Glutamic oxaloacetic transaminase;GOT)、麩丙酮酸轉氨酶(Glutamic pyruvic transaminase; GPT)、血中尿素氮(Blood urea nitrogen;BUN)、肌酸酐(Creatinine;Cre)、乳酸去氫酶(Lactic dehydrogenase;LDH)、肌酸磷激酶(Creatine phosphokinase;CPK)及乳酸(Lactate)。在失血後第1、9及18小時分別檢測血清中的細胞激素濃度,包括TNF-α及IL-6。失血後48小時,犧牲大鼠,取出肝、腎、肺及小腸行病理切片檢查。在第二部分的內毒素血症研究,又分為兩組子實驗,分別是1.內毒素血症與EPO 300單位/公斤的實驗;2.內毒素血症與EPO 1000單位/公斤的實驗。在第一組子實驗中,大鼠在注射LPS前,先由靜脈給予EPO 300單位/公斤。接著將大腸桿菌的LPS(20毫克/公斤)經靜脈注射20分鐘誘發內毒素休克。LPS給予後的48小時內持續記錄MAP及HR。在LPS給予前1小時及LPS給予後第1、3、6、9、12、18、24及48小時檢驗血清中生化指標,包括GOT、GPT、BUN、Cre、LDH、CPK等。在LPS給予後第一小時檢查血清發炎前細胞激素濃度,包括TNF-α、IL-6及IL-1β。內毒素血症後48小時,犧牲大鼠,取出肝、腎、肺及小腸行病理切片檢查。在第二組子實驗中,將EPO劑量提高到1000單位/公斤,在相同時間點檢測生化指標,包括GOT、GPT、BUN、Cre、LDH、CPK及發炎前細胞激素濃度,包括TNF-α及IL-6。內毒素血症後48小時,犧牲大鼠,行肝、腎、肺及小腸的病理切片檢查。
結果顯示,在第一部分的HS研究方面,大鼠的HS有意義的使HR、血清中的GOT、GPT、BUN、Cre、LDH、CPK、lactate、TNF-α、IL-6上升,而血色素及MAP下降。這些HS的大鼠,若預先給予EPO 300單位/公斤會改善其存活率、提升MAP、減少心搏過速、降低代表器官損傷的指數,並抑制TNF-α、IL-6的釋放。在第二部分內毒素休克模型的第一組子實驗中,LPS使血清中GOT、GPT、BUN、Cre、LDH、CPK、TNF-α、IL-6、IL-1β濃度及HR明顯上升,而MAP明顯下降。在內毒素休克前給予EPO 300單位/公斤會使代表器官損傷的指標,如GOT、GPT、BUN、Cre、LDH、CPK、及發炎前細胞激素,如TNF-α、IL-6及IL-1β上升得更高,而MAP及HR則不受影響。病理切片顯示,EPO 300單位/公斤會加重清醒大鼠內毒素休克誘發的肝、腎、肺及小腸的損傷。而第二組子實驗中,EPO 1000單位/公斤同樣的會使GOT、GPT、BUN、Cre、LDH、CPK及TNF-α、IL-6上升的更高,而MAP及HR不受影響。病理切片顯示,EPO 1000單位/公斤同樣會加重清醒大鼠內毒素休克誘發的肝、腎、肺及小腸的損傷。
結論顯示,在清醒大鼠模式下,HS前給予EPO 300單位/公斤會抑制血清TNF-α、IL-6的釋放,降低代表器官傷害的指數,從而減緩HS引發的器官損傷。但是,內毒素休克前給予EPO 300單位/公斤或1000單位/公斤反而會增加發炎前細胞激素的釋放,同時會加重器官損傷的程度。
Hemorrhagic shock (HS) causes haemodynamic instability and decrease in oxygen delivery and tissue perfusion. At the molecular level, the nuclear factor-κB (NF-κB) is activated and involved in apoptosis and the inflammatory cascade. Overwhelming production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) can lead to multiple organ dysfunction and death. On the other hand, in the gram negative bacteria infection, the endotoxin or lipopolysaccharide (LPS) can also trigger the production of TNF-α, IL-6 and IL-1β, resulting in organ failure. Erythropoietin (EPO) has been found to interact with its receptor, expressed in a wide variety of non-hematopoietic tissues, to induce a range of pleiotropic cytoprotective actions. The study includes two parts, investigating the effects of EPO on organ damage induced by HS and endotoxemia in conscious rats.
In the HS study ( 1st part ), rats received an intravenous injection of 300 U/kg of EPO followed by HS via withdrawal of 60% of total blood volume from the femoral arterial catheter (6 ml/100 gm body weight) over 30 min. Mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 18 hrs after the start of blood withdrawal. Haemoglobin and levels of biochemical parameters, including glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), Creatine phosphokinase (CPK) and lactate were measured at 30 min before induction of HS and 0, 1, 3, 6, 9, 12 and 18 hr after HS. Cytokine levels, including TNF-α and IL-6, in serum were measured at 1, 9 and 18 hr after HS. The liver, kidney, lung and small intestine were removed for pathology assessment at 48 hr after HS. In the endotoxin shock study ( 2nd part ), it was subdivided into two sections. In the 1st section, the 300U/kg of EPO was given intravenously, followed by endotoxin shock induced by intravenous injection of 20 mg/kg of Escherichia coli LPS in conscious rats. MAP and HR were continuously monitored for 48 hrs after LPS administration. Levels of GOT, GPT, BUN, Cre, LDH and CPK were measured at 1 hr before LPS administration and 1, 3, 6, 9, 12, 18, 24 and 48 hr after endotoxin shock. Serum TNF-α, IL-6 and IL-1β level was measured at 1 hr after sepsis. The liver, kidney, lung and small intestine were taken for pathologic examination at 48 hr after endotoxin shock. In the 2nd section of endotoxemia study, the 1000U/kg of EPO was given instead of 300U/kg of EPO. The serum levels of GOT, GPT, BUN, Cre, LDH, CPK, TNF-α and IL-6 were checked at the same time points. The pathology of liver, kidney, lung and small intestine was examined at 48 hr after endotoxemia.
In the 1st part of the study, HS significantly increased HR, serum GOT, GPT, BUN, Cre, LDH, CPK, lactate, TNF-α and IL-6 levels, but decreased haemoglobin and MAP in rats. Pre-treatment with EPO improved survival rate, preserved the MAP, decreased the tachycardia and markers of organ injury, and suppressed the release of TNF-α and IL-6 after HS in rats. EPO ameliorated organ damage induced by HS in conscious rats. However, in the 2nd part of the study, endotoxin shock significantly increased serum GOT, GPT, BUN, Cre, LDH, CPK, TNF-α, IL-6, IL-1β levels and HR, while it decreased MAP. The 300U/kg or 1000U/kg of EPO further increased the markers of organ injury (GOT, GPT, BUN, Cre, LDH, CPK), pro-inflammatory cytokines, but did not affect MAP and HR after LPS. EPO disserved endotoxin shock-induced organ damage in conscious rats.
In conclusion, pre-treatment with EPO suppresses the release of serum TNF-α and IL-6 and decreases the levels of markers of organ injury, ameliorating HS-induced organ damage in conscious rats. However, pre-treatment with 300U/kg or 1000U/kg of EPO increases the release of pro-inflammatory cytokines, aggravating endotoxin shock-induced markers of organ injury in conscious rats.
誌謝...I
中文摘要... II
英文摘要... IV
縮寫表...VI
論文目錄...X
圖表目錄...... XII
附錄目錄...XIV
第一章 緒論 ...1
第一節 研究背景與動機 ...2
第二節 研究問題與目的 ...4
第二章 文獻查證 ...5
第一節 失血性休克與炎症反應 ...6
第二節 敗血症與炎症反應 ...12
第三節 紅血球生成素的作用機轉 ...19
第三章 以清醒大鼠模式探討紅血球生成素對於失血性休克引發的器官損傷之影響...22
第一節 研究背景 ...23
第二節 材料與方法...24
第三節 統計與分析...27
第四節 結果 ...28
第五節 討論與結論...31
第四章 以清醒大鼠模式探討紅血球生成素對於內毒素血症引發的器官損傷之影響...34
第一節 研究背景 ...35
第二節 材料與方法 ...36
第三節 統計與分析 ...39
第四節 結果...40
第五節 討論與結論...43
第五章 總結論...46
第一節 研究結果總結...47
第二節 討論 ...49
參考文獻 ...52
圖表 ...63
附錄...91
已發表論文相關著作...101
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