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標題: | 免疫和發炎反應在臨床使用葉克膜之病人的預後意義 Prognostic significance of immune/inflammatory responses in patients receiving extracorporeal membrane oxygenation |
作者: | Chia-Hsiung Liu 柳嘉雄 |
指導教授: | 周祖述(Tzuu-Shuh Jou) |
關鍵字: | 葉克膜,心因性休克,急性呼吸窘迫症,過氧化物還原?,全身性發炎反應症候群,先天性免疫, ECMO,cardiogenic shock,ARDS,Prdx1,SIRS,innate immunity, |
出版年 : | 2017 |
學位: | 博士 |
摘要: | 葉克膜提供心肺衰竭有效的呼吸及循環系統支持,近幾年在心因性休克及急性呼吸窘迫症病人的使用大幅增加,然而,儘管新型儀器設備的改良及加護病房照護的改善,葉克膜病人總體死亡率仍居高不下。因此,了解造成不良預後的機制是改善病人選擇標準及精進介入治療方法的重要課題。
使用葉克膜可能引起缺血再灌流的傷害,與先天性免疫系統廣泛被激活有關,造成全身性發炎反應症狀,如果不受控制,將導致多重器官衰竭而死亡。本研究中,我們偵測血液中組織傷害所釋放之damage associated molecular pattern (DAMP) 分子第一型過氧化物還原酶Peroxiredoxin 1 (Prdx1)、發炎細胞激素、免疫細胞族群、及單核球表面先天性免疫受體 (TLR4 和CD14) 在病人裝置葉克膜前後的變化,來闡明全身性發炎反應的病因及找出可能的預後因子,以利葉克膜的妥善使用。 在心因性休克病人中,結果顯示葉克膜支持的早期,血液中Prdx1的濃度增加不僅比其他發炎激素更早達到高峰,而且血液中較高的Prdx1濃度可預測不良預後。Prdx1濃度和缺氧指標carbonic anhydrase IX 、乳酸及多項發炎激素濃度呈現正相關。人類單核球細胞的體外試驗也顯示,缺氧後再充氧會強化Prdx1所誘導的發炎激素產生,也使單核球細胞釋出Prdx1。進一步外加Prdx1抗體則可抑制此發炎激素 IL-6 的產生。這些結果說明葉克膜支持的早期,心因性休克病人血液中Prdx1的釋出可能和全身性發炎反應的形成及臨床不良預後有關。 急性呼吸窘迫症病人在裝置葉克膜前及隨後的六個小時,血液中高濃度的IL-10 是這些病人不良預後的潛力標誌物。這些在葉克膜支持初期所釋放出來的 IL-10濃度和重症加護病房常用的風險評估分數呈現正相關。高濃度IL-10可能涉及較慢的免疫細胞族群的比例恢復,如單核球細胞CD14+CD16+、CD14+TLR4+ 和調節性T細胞 T regulatory cells。從基因體變異的觀點,此高濃度IL-10和其基因啟動子區域的兩個多形性核苷酸 (–592C and –819C) 有關。 根據精準醫療的原則,我們的發現提供了心因性休克和急性呼吸窘迫症而裝置葉克膜病人所需要的治療預後和機制的訊息,將有助於未來發展新的治療策略。 Extracorporeal membrane oxygenation (ECMO) provides effective respiratory and circulatory support for cardiopulmonary arrest, and has been increasingly used for patients with cardiogenic shock and acute respiratory distress syndrome (ARDS) refractory to conventional therapies. However, the overall prognosis of these patients, despite significant advances in quality of the devices and in the management of intensive care unit, remains grave. Therefore, understanding the underlying mechanisms which contribute to poor clinical outcomes is a pivotal issue to improve patient selection as well as further refine this therapeutic intervention. An ischemia/reperfusion injury testified during ECMO is systemic inflammatory response syndrome (SIRS) which is associated with the widespread activation of the innate immunity, which, if unconstrained, would result in multiple organ failure and eventual mortality. To understand the underlying mechanisms which contribute to SIRS and identify potential biomarker of predicting value for appropriate use of ECMO, plasma damage associated molecular pattern (DAMP) molecule peroxiredoxin 1 (Prdx1), inflammatory cytokines, immune cell populations, and signaling receptors of DAMP (TLR4 and CD14) were examined during the early and subsequent disease courses of adult patients who received ECMO support. In patients with cardiogenic shock, Prdx1 not only peaks earlier than all the other cytokines we study during the initial course of ECMO installation, but also predicts a worse outcome in patients who had higher initial Prdx1 plasma levels. The Prdx1 levels in patients positively correlate with hypoxic markers carbonic anhydrase IX and lactate, and inflammatory cytokines. An in vitro study demonstrates that hypoxia/re-oxygenation induced Prdx1 release from human monocytes and enhances the responsiveness of the monocytes in Prdx1-induced cytokine secretions. Furthermore, functional inhibition by Prdx1 antibody implicates a crucial role of Prdx1 in hypoxia/re-oxygenation-induced IL-6 secretion. These findings indicate that Prdx1 release during the early phase of ECMO support in cardiogenic shock patients is associated with the development of SIRS and poor clinical outcomes. For ARDS patients, high IL-10 level at the time of ECMO installation and during the first 6 hours after ECMO support stands as a promising biomarker associated with grave prognosis. The initial IL-10 level is correlated to other conventional risk evaluation scores as a predictive factor for survival, and furthermore, elevated IL-10 levels are also related to a delayed recovery of certain immune cell populations such as CD14+CD16+, CD14+TLR4+ monocytes, and T regulatory cells. Genetically, high interleukin-10 is associated to two polymorphic nucleotides (–592C and –819C) at the interleukin-10 gene promoter area. Our finding provides prognostic and mechanistic information on the outcomes of cardiogenic shock and severely respiratory distressed patients, and potentially paves the strategy to develop new therapeutic modality based on the principles of precision medicine. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67725 |
DOI: | 10.6342/NTU201701238 |
全文授權: | 有償授權 |
顯示於系所單位: | 臨床醫學研究所 |
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