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系統識別號 U0007-2006201717373900
論文名稱(中文) 給予魚油乳劑可減輕敗血症及下肢缺血再灌流小鼠發炎反應及遠端腎臟之損傷
論文名稱(英文) Fish oil-based fat emulsion reduces inflammatory responses and remote kidney injury in murine models of both septic peritonitis and hind limb ischemia/reperfusion injury
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) 施瑞明
研究生(英文) Juey-Ming Shih
學號 D507102005
學位類別 博士
語文別 英文
口試日期 2017-06-02
論文頁數 98頁
口試委員 指導教授-葉松鈴
委員-陳玉華
委員-黃士懿
委員-許瑞芬
委員-蔡帛蓉
中文關鍵字 腎損傷  敗血症  缺血再灌流  魚油乳劑  發炎反應 
英文關鍵字 acute kidney injury  polymicrobial sepsis  ischemic reperfusion injury  fish oil lipid 
學科別分類
中文摘要 急性腎損傷(acute kidney injury, AKI)是重症病人常見的症狀,臨床上造成AKI 的原因很多,包括:敗血症、重大手術、缺血性休克和藥物引致等,本研究主要在探討營養素介入對兩種外科加護病房常發生的AKI,即敗血症及嚴重下肢缺血引致腎損傷的影響。雖然造成這兩種腎損傷的機制不同,但發炎反應是其共通的病理特徵。魚油是富含n-3 多元不飽和脂肪酸(PUFA)的油脂,過去的研究顯示魚油有免疫調節及抗發炎的特性,因此魚油的添加可能對這兩種臨床狀況所引起的全身性發炎反應及腎損傷具有保護作用。本研究利用敗血症及下肢缺血的小鼠模式,來探討魚油乳劑的補充對腎臟發炎和組織損傷的影響及其在臨床的應用性。本研究分成兩部分,第一部分探討魚油乳劑對腹膜炎引致敗血症腎損傷的保護作用。將小鼠在引致敗血症後以腹腔注射不同脂肪乳劑及生理食鹽水,分別於24 及72 小時犧牲,收集血液、腹腔沖洗液及腎臟組織做分析,結果顯示相較於生理食鹽水,魚油乳劑介入可降低腎臟發炎相關因子,增加 heat shock protein 及peroxisome proliferator-activated receptor-γ 之基因表現量,並改善腎組織損傷。第二部分以拉力4.5 oz 之牙科矯正用橡皮筋,綑綁在小鼠左後肢大轉子上方120 分鐘,造成左後肢缺血,來探討魚油在缺血前或後介入對再灌流後72 小時肌肉組織及遠端腎臟損傷的影響,結果顯示魚油介入可降低肌肉損傷之指標,而魚油在缺血後介入更可緩解缺血再灌流引致之腎臟發炎反應。由兩部分之實驗結果顯示,魚油介入可藉由調節發炎介質表現量,減少器官組織白血球的浸潤,改善因敗血及缺血再灌流引致之腎臟發炎及損傷,本研究結果可做為臨床上休克及創傷引致腎損傷病人營養支持上的重要參考依據。
英文摘要 Acute kidney injury (AKI) is common among critically ill patients and leads to significant mortality. The etiologies of AKI are diverse. Common causes include sepsis, major surgery, cardiogenic shock, hypovolemic shock, and nephrotoxic drugs. This study focused on two of the more insidious forms of AKI that are of concern in the shock-and-trauma intensive care unit, namely, sepsis-induced AKI and ischemia reperfusion (IR)-induced AKI. Although the two renal injuries involve very different mechanisms, inflammation is central to their pathophysiologies. Since fish oil has been well known for its anti-inflammatory benefits, it is postulated that fish oil supplementation may have a role in protecting the kidneys in these two situations. This study utilized murine models of sepsis and limb ischemia to explore the applicability of clinically available fish oil containing lipid emulsions (FO) in renal protection. The first part of this study focused on the renal-protective effects of fish oil in AKI induced by cecal ligation and puncture (CLP), a model of septic peritonitis. The animals were sacrificed at 24h or 72h post-CLP and assessed for the extent of sepsis-induced renal injury. Blood, peritoneal lavage fluid, and kidney samples were analyzed for evidence of local and systemic inflammation, which could be modulated by fish oil administration. The second part of the study investigated the renal-protective effects of FO in AKI as a consequence of prolonged unilateral limb ischemia. Mice were subjected to 120 min of unilateral hindlimb ischemia-reperfusion injury by applying a 4.5-oz orthodontic rubber band. The effects of FO on local skeletal muscle and remote renal injury at 72h reperfusion were assessed. The results showed that FO supplementation diminished serologic markers of muscle damage following IR injury. In addition, FO given after IR injury was able to significantly downregulate the inflammation seen in IR-induced remote kidney injury. These findings suggest that by modulating cytokine/chemokine expressions and altering leukocyte recruitment, FO may ameliorate the systemic inflammatory response, and protect against remote kidney injury from both sepsis and limb IR injury. The results from these studies may provide some insight for the clinical applicability of FO in shock-and-trauma patients who are susceptible to AKI.
論文目次 Table of Contents
中文摘要...................................................6
Abstract...................................................7
Chapter 1 Background......................................9
1.1 Clinical Relevance Statement..........................9
1.2 Epidemiology of AKI and its Clinical Impact...........9
1.3 Sepsis and Acute Kidney Injury.......................10
Table 1.3-1. RIFLE classification of Renal Injury.........11
1.4 The Septic Inflammatory Response.....................12
1.5 Pathogenesis of SAKI.................................18
1.6 Ischemic Limb and Acute Kidney Injury................19
1.7 IR Inflammatory Response.............................20
1.8 Pathogenesis of Acute Renal Failure After Lower Limb IR Injury.................................................24
1.9 Fish Oil Modulates the Inflammatory Response.........25
Chapter 2 Study Objective................................28
Chapter 3 Fish Oil-Based Fat Emulsion Reduces Acute Kidney Injury and Inflammatory Response in Antibiotic-Treated Polymicrobial Septic Mice.................................29
3.1 Introduction.........................................29
3.2 Materials and Methods................................31
Table 3.2-1. Outline of Study Groups and Design...........33
3.3 Results..............................................40
Table 3.3-1. Fatty acid composition of the fish-oil based (FO) and mixed oil (MO) lipid emulsion (% of total FA)....44
Table 3.3-2. Primer sequences used in the quantitative real-time reverse-transcription polymerase chain reaction assays....................................................45
Table 3.3-3. Plasma concentrations of biochemicalmarkers..46
Table 3.3-4. Inflammatory mediator concentrations in plasma and PLF...................................................47
Figure 3.3-1. Proportion of neutrophils, monocytes, and T cells in blood............................................48
Figure 3.3-2. Percentage of Th1, Th17, and Tregs in blood.49
Figure 3.3-3. Expression of Inflammation-Related Genes in renal tissues.............................................50
Figure 3.3-4. Histology and quantification of kidney tissues at 72 h after CLP.................................51
3.4 Discussion...........................................52
3.5 Conclusion...........................................56
Chapter 4 Fish Oil-Based Lipid Emulsion Reduces Skeletal Muscle and Kidney Injury in Mice Subjected to Unilateral Hind Limb Ischemia/Reperfusion............................58
4.1 Introduction.........................................58
4.2 Materials and Methods................................59
Table 4.2-1. Outline of Study Groups and Design...........62
4.3 Results..............................................67
Table 4.3-1. Primer sequences used in the quantitative real-time reverse-transcription polymerase chain reaction assays....................................................71
Table 4.3-2. Plasma biochemical markers at days 0 and 1...72
Table 4.3-3. Plasma concentrations of biochemical markers at day 3..................................................73
Figure 4.3-1. Distribution of leukocytes in blood.........74
Figure 4.3-2. Distribution of leukocytes in muscle........76
Figure 4.3-3. Expression of inflammation-related genes in muscle tissues............................................77
Figure 4.3-4. Expression of inflammation-related genes in kidney at days 0 and 1....................................78
Figure 4.3-5. Expression of inflammation-related genes in renal tissues at day 3....................................79
Figure 4.3-6. Histology of the kidney tissues.............80
4.4 Discussion...........................................81
4.5 Conclusion...........................................86
Chapter 5 Summary........................................88
References................................................89
Publications..............................................98
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