血清中膠蛋白分解酵素酶-9上升的機轉在院外心臟停止病人之預後及其臨床應用

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题名:	血清中膠蛋白分解酵素酶-9上升的機轉在院外心臟停止病人之預後及其臨床應用 The mechanism of serum matrix metalloproteinases-9 elevation and its clinical application in patients with Out Hospital Cardiac Arrest
作者:	林雅惠;Ya-Hui Lin
贡献者:	醫學院臨床醫學研究所碩士班
关键词:	基質膠蛋白酶-9(MMP-9);腫瘤壞死因子-α(TNF-α);院外心臟心跳停止(OHCA);細胞介白素-8(IL-8);AKT;細胞外訊息調控激酶（ERK）;OHCA (Out Hospital CardiacArrest );MMP-9( Matrix Metalloproteinase-9);TNFα(Tumor necrosis factor-α);IL-8 (Interleukin-8);AKT（v-akt murine thymoma viral oncogene homolog﹞;ERK(Extracellular signal-Regulated Kinase)
日期:	2009
上传时间:	2010-09-29 12:17:16 (UTC+8)
摘要:	院外心臟心跳停止（Out Hospital Cardiac Arrest ,OHCA）是心臟組織缺血及被破壞所產生之結果，而發炎反應及心臟之前基質膠蛋白酶-9 (MMP-9)是造成心臟衰竭的一重要關鍵；已有些研究證明在心臟缺血事件發生後，血清中MMP-9的活性會在心臟疾病發作後的前12小時即開始增加。我們假設OHCA的病人經由心肺復甦術(CPR)後，其血清中TNF-α濃度會上升，而誘導IL-8及MMP-9之表現。此研究之目的為上述之假設及要探討OHCA病人CPR時給予epinephrine之劑量與血清中TNF-α、IL-8及MMP-9濃度的相關性。在體外研究，吾人以大鼠H9c2心肌細胞為標的，來探討H9c2心肌細胞受TNF-α的作用後，IL-8及MMP-9之變化及其訊息傳導路徑。我們收集30位OHCA病人及10位健康的對照組血清，分析血清中TNF-α、IL-8及MMP-9濃度及MMP-9活性。CPR後24小時內死亡者稱為早期死亡(ED)，血清中TNF-α、IL-8及MMP-9濃度以ELISA方法測得，MMP-9活性以zymography測得。訊息傳導路徑則是以西方墨點法探討，定量m-RNA表現則以及時定量聚合酶連鎖反應來分析。發現結果在早期死亡之OHCA病人其血清中TNF-α、IL-8及MMP-9濃度明顯增加具統計性差異 (p<0.05)。特別值得注意，CPR中及後epinephrine使用之總劑量與CPR後血清中TNF-α、IL-8及MMP-9濃度之上升有密切相關性。CPR中過度給予epinephrine會誘導血清中IL-8及MMP-9濃度的增加而可能對OHCA病人造成傷害。在H9c2細胞體外研究發現，TNF-α會增強ERK1/2、AKT磷酸化，及上調控MMP-9 m-RNA表現之作用，具統計差異。總結：在早期死亡之OHCA病人中，血清中TNF-α、IL-8及MMP-9濃度會增加。CPR中及後過度給予epinephrine會誘導血清中IL-8及MMP-9濃度的增加而可能對OHCA病人造成傷害。於體外試驗發現，TNF-α會增強H9c2細胞中ERK1/2及AKT磷酸化及MMP-9的表現。關鍵字：基質膠蛋白酶-9(MMP-9)、腫瘤壞死因子-α(TNF-α)、院外心臟心跳停止(OHCA) 、細胞介白素-8(IL-8) 、AKT 、細胞外訊息調控激酶（ERK） Out Hospital Cardiac Arrest (OHCA) is the result of both ischemia and the destruction of cardiac tissue. The inflammatory response and cardiac pro-matrix metalloproteinase (MMP) is critical to the development of heart failure. Some studies demonstrated that MMP-9 activity will increase within the first twelve hours after the ischemic event. We hypothesize that serum TNF-α level increased in patient with OHCA after cardiopulmonary resuscitation(CPR) then induce the expression of TNF-α,IL-8 and MMP-9. The aims of this study are to investigate the serum levels of TNF-α,IL-8 and MMP-9, and the correlation to the total dose of epinephrine administered in patients of OHCA during and after CPR. In vitro we observed the IL-8 and MMP-9 production in H9c2 cells after stimulated by TNF-α and explored the mechanism of signal transduction pathway. We collected thirty patients with OHCA and ten age and sex matched healthy control and analyzed the serum level of IL-8, TNF-α, and MMP-9. Death within twenty four hours after CPR was defined as early death (ED). Serums TNF-α, IL-8 and MMP-9 levels were measured by the ELISA method and the MMP-9 activity was measured by Zymography. Signal transduction pathway, was examined by western blotting, quantitative m-RNA expression was measured by real-time PCR. The results showed that serum TNF-α,IL-8 and MMP-9 levels increased in ED of OHCA patients with significantly statistical difference (p<0.05).It is especially noteworthy that the total dose of epinephrine administered during and after CPR was closely related to the elevation of serum TNF-α,IL-8 and MMP-9.The increase in serum IL-8 ,MMP-9 induced by excessive administration of epinephrine might be harmful in OHCA patients after CPR. In vitro,TNF-α could enhance the phosphorylation of ERK1/2 and AKT in the H9c2 cells. Expression of MMP-9 m-RNA was up-regulated by TNF-α and the stimulation results exhibited statistical difference. In conclusion, serum TNF-α,IL-8 and MMP-9 levels increased in ED of OHCA patients. Elevation of serum TNF-α,IL-8 and MMP-9 levels ,induced by excessive administration of epinephrine might be harmful in OHCA patients after CPR. In vitro, TNF-α could enhance the phosphorylation of ERK1/2 and AKT in H9c2 cells and MMP-9 mRNA expression. Key word：OHCA (Out Hospital CardiacArrest ), MMP-9 ( Matrix Metalloproteinase-9) TNFα (Tumor necrosis factor-α) IL-8 (Interleukin-8) AKT（v-akt murine thymoma viral oncogene homolog） ERK (Extracellular signal-Regulated Kinase)
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