系統識別號 U0007-2006201717201400
論文名稱(中文) 麩醯胺及魚油乳劑對小鼠後肢缺血再灌流所造成肌肉及遠端器官損傷的保護作用
論文名稱(英文) The protective effect of glutamine and fish oil-based lipid emulsion on skeletal muscle and remote organ injury in a mouse hind limb ischemia/reperfusion model
校院名稱 臺北醫學大學
系所名稱(中) 保健營養學研究所
系所名稱(英) Graduate Institute of Nutrition and Health
學年度 105
學期 2
出版年 106
研究生(中文) 施耀明
研究生(英文) Yao-Ming Shih
學號 D507102004
學位類別 博士
語文別 英文
口試日期 2017-06-02
論文頁數 111頁
口試委員 委員-許瑞芬
中文關鍵字 缺血再灌流  麩醯胺  魚油乳劑  肺組織損傷  發炎介質 
英文關鍵字 ischemia reperfusion injury  glutamine  fish oil lipid emulsion  remote lung 
中文摘要 急性肢體缺血常發生於創傷或肢體重建手術,缺血的組織再重新獲得血液灌流是維持組織生理功能所必需,但當缺血組織再灌流血液時會引致大量自由基產生,自由基及其引發的免疫細胞活化,會造成細胞膜損傷、細胞凋亡、組織壞死、並使器官組織喪失其功能,通常也伴隨全身性的發炎反應,並造成遠端器官的傷害。營養支持對肢體缺血再灌流的重症病人非常重要,但理想的營養素配方組成目前仍有待研發。本研究介入兩種特殊營養素,來探討這些營養素對缺血再灌流引致的白血球活化及缺血肌肉與遠端器關損傷的影響。本研究共分為兩個部分,第一部分以尾靜脈注射之方式在小鼠後肢缺血90分鐘,血液再灌流之前注入麩醯胺 (glutamine, GLN),在灌流4及24小時後觀察血液及組織的變化。結果顯示,GLN的給予可在再灌流的早期和晚期低肌肉發炎反應介質基因表現、血中巨噬細胞比例及血中Interleukin-6 的濃度,肺的組織切片也顯示其受損較為輕微。此結果顯示在缺血組織再灌流之前立即給予GLN,可降低缺血再灌流引致的發炎反應,並減輕局部和遠端器官的損傷。第二部分則是在小鼠後肢缺血再灌流之前給予富含n-3多元不飽和脂肪酸(PUFA)的魚油脂肪乳劑,來探討n-3 PUFA對缺血再灌流引致的細胞激素分泌及白血球活化的影響,希望能了解魚油乳劑介入對再灌流後血中各不同白血球的分佈,以及巨噬細胞極化轉變(polarization switch)的影響。結果顯示,在再灌流後24小時,在魚油給予的組別局部和全身性發炎反應介質的表現量較低,同時血中發炎性Ly6ChiCCR2hi單核球的百分比,及肌肉中M1/M2的比例均較生理食鹽水組為低,顯示魚油給予的組別發炎反應較為減輕。這兩個實驗的結果可提供臨床上肢體缺血病人利用GLN和n-3 PUFA做為營養支持的重要參考依據。
英文摘要 Acute ischemia of limb is a frequent clinical entity that may be encountered in the practice of traumatic surgery or reconstructive. Ischemic reperfusion (IR) injury often occurs in trauma patients suffering from critical limb ischemia. Re-establishment of blood flow to ischemic
tissue is necessary to maintain metabolic requirements of the tissue; however, the reperfusionof oxygenated blood to ischemic tissue may induce local tissue and remote organ injury. For critical patients with IR injury, nutrition support is essential and the optimal formulation is still being investigated. In this study, we administered 2 specific nutrients to investigate the possible protective effect of the nutrients on IR-induced leukocyte activation and the affected muscle as well as distant organ injury. There are 2 parts in this study. The first part involves
administering intravenous glutamine (GLN) to C57BL6 mice after 90 minutes of ischemia just before reperfusion in a murine unilateral hind limb IR model. The results showed that IRinduced muscle inflammatory mediator expression, blood macrophage percentage, and plasma interleukin-6 levels all declined at either early or late phases of reperfusion when GLN was administered. These findings suggest that GLN administration immediately after sublethal limb ischemia reduces the inflammatory response and offer tissue protection both locally and systemically. The second part of this study investigated the effects of an n-3 polyunsaturated fatty acid (PUFA) containing fish oil (FO) lipid emulsion on the modulation of cytokine/chemokine expressions and alteration of leukocytes activation in order to understand the recruitment pattern of various leukocyte subpopulations and the status of macrophage polarization switch during the period after reperfusion. The results showed FO pretreatment suppressed the local and systemic expression of several IR-induced proinflammatory
mediators. Additionally, FO-pretreated group had lower blood Ly6ChiCCR2hi monocyte percentage and muscle M1/M2 ratio than the saline group at 24 h after reperfusion.
The results of these 2 experiments may provide some evidence for the clinical application of GLN and n-3 PUFA in patients with critical limb ischemia.
論文目次 中文摘要
Chapter 1 Acute Limb Ischemia 7
Acute Limb Ischemia 7
1.1 Ischemia reperfusion injury 7
Figure 1.1 Scheme of biochemical events involved in ischemia and reperfusion 8
1.2 Therapeutic strategies for acute limb ischemia 10
Figure 1.2 Selective management of acute ischemic limb 11
Table 1.2 Intervention strategies to reduce postischemic skeletal muscle injury 12
Chapter 2 Reperfusion injury and Inflammation 14
2.1 Innate immunity 14
Figure 2.1-1 Hematopoietic stem cell-derived lineages 15
Figure 2.1-2 Interactions between leukocyte and endothelium in skeletal ischemia
reperfusion injury 17
Figure 2.1-3 Leukocyte Rolling, Adhesion, Diapedesis, and Migration 18
Table 2.1-1 Common adhesion molecules involved in leukocyte-endothelial interaction 19
Table 2.1-2 Chemokines 21
Table 2.1-3 Chemokine receptors 23
Table 2.1-4 Summary of main sources and effects of cytokines 25
2.2 Inflammatory cascades in reperfusion injury 27
Figure 2.2-1 Endothelium-dependent mechanisms of IR injury 29
Figure 2.2-2 The role of CXC chemokines in ischemic tissues 31
Figure 2.2-3 The role of CC chemokines in ischemic tissues 33
Figure 2.2-4 Mechanisms underlying the development of remote organ injury 36
2.3 Glutamine and inflammation 37
2.4 Fish-oil containing lipid emulsion and inflammation 40
Chapter 3 Objective of the Experiment 44
Purpose of Study 44
3.1 Effect of IV GLN administration on inflammatory reaction and organ protection after sublethal unilateral limb IR injury 44
3.2 Effect of IP Fish oil-based lipid emulsion pretreatment on muscle leukocyte chemotaxis and blood leukocyte distribution after sublethal unilateral limb IR injury 45
Chapter 4 Effect of Intravenous Glutamine Administration on the Inflammatory Reaction and Organ Protection after sublethal unilateral limb ischemia in a murine model of sublethal ischemia-reperfusion injury 47
4.1 Materials and Methods 47
4.2 Results 56
Table 4.2-1 Sequences of oligonucleotide primers used in PCR amplification 59
Table 4.2-2 Concentration of IL-6 in plasma 60
Table 4.2-3 Thiobarbituric acid reactive substance (TBARS) levels in muscle tissues 60
Figure 4.2-1 Blood leukocyte distribution and expression of adhesion molecules and chemokine receptors by leukocytes 61
Figure 4.2-2 mRNA expressions of inflammatory genes in muscle tissues 62
Figure 4.2-3 Percentage of leukocytes in bronch-oalveolar lavage fluid 63
Figure 4.2-4 Histology of muscle tissue 64
Figure 4.2-5 Histology of the lung tissue 65
4.3 Discussion 66
4.4 Conclusion 73
Chapter 5 Effect of Intraperitoneal Fish oil-Based Lipid Emulsion Pretreatment on muscle leukocyte chemotaxis and blood leukocyte distribution in a murine model of
sublethal ischemia-reperfusion injury 74
5.1 Materials and Methods 74
5.2 Results 81
Table 5.2-1 Primer sequences used in the qRT-PCR assay 84
Table 5.2-2 Plasma concentrations of the cytokines 85
Figure 5.2-1 Distribution of blood leukocytes 86
Figure 5.2-2 Expression of anti- and pro-inflammatory cytokines and chemokines in muscle tissues 87
Figure 5.2-3 Distribution of leukocytes and M1 to M2 ratio in muscle 88
Figure 5.2-4 Expression of Pro-inflammatory and Anti-inflammatory mediator mRNAs in lung tissue 89
5.3 Discussion 90
5.4 Conclusion 94
Chapter 6 Summary 95
References 96
Publications 111
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