臺灣博碩士論文加值系統

小腸缺血再灌流引發之腸道損傷常導致全身性發炎及多重器官衰竭，進而造成死亡。動物實驗證實，小腸缺血前補充麩醯胺酸及精胺酸，可增加動物於灌流後的存活率，並促進腸黏膜組織的修復，但此作用未見於臨床上缺血及再灌流後的補充。研究亦指出，瓜胺酸的補充可增加體內精胺酸的合成，且無一氧化氮(NO)過度產生的問題，但相關的研究仍不多見。因此，本研究利用小腸缺血之大鼠模式模擬臨床上小腸缺血再灌流誘導之急性及慢性損傷，以比較灌流前及灌流後口服麩醯胺酸、精胺酸及瓜胺酸補充劑改善腸道損傷的效果。雄性Wistar大鼠分為九組，一組正常對照組，其餘各組施予上腸繫膜動脈阻塞手術60分鐘以誘導小腸缺血，並於灌流3或24小時後將大鼠犧牲。動物於灌流前15分鐘及灌流後3、9及21小時，分別給予安慰劑、麩醯胺酸、精胺酸或瓜胺酸。結果顯示，灌流3及24小時後，大鼠血漿發炎物質NO、間白素(IL)-6及干擾素(IFN)-r顯著增加，且小腸發炎物質IFN-r及小腸黏膜蛋白質含量顯著下降。但小腸缺血再灌流3小時後，血漿麩醯胺酸、瓜胺酸、精胺酸與腫瘤壞死因子(TNF)-a濃度及小腸瓜胺酸含量、細胞凋亡指數、骨髓過氧化酶(MPO)活性與神經型一氧化氮合成酶(nNOS)蛋白質表現量顯著增加，且小腸型態及質量、腺窩細胞增生及核內轉錄因子(NF)-kB比值顯著下降。而灌流24小時後，大鼠肝臟重量、血清白蛋白濃度、肝臟及腎臟功能指標及白血球數目顯著增加，且小腸TNF-a、IL-6含量與神經型及誘導型一氧化氮合成酶(nNOS)蛋白質表現量顯著下降。補充麩醯胺酸、精胺酸及瓜胺酸顯著減緩小腸細胞凋亡、nNOS蛋白質表現量及再灌流3小時之血漿IL-6的增加。再灌流3小時之大鼠，補充麩醯胺酸顯著減緩血漿TNF-a及小腸黏膜蛋白質的降低；補充精胺酸顯著改善小腸腺窩深度及肌肉層厚度的降低，但降低小腸腺窩細胞增生；而補充瓜胺酸顯著改善小腸型態及質量的降低，並減緩血漿麩醯胺酸、NO、TNF-a及小腸MPO活性的增加。再灌流24小時之大鼠，補充麩醯胺酸、精胺酸及瓜胺酸顯著減緩血漿NO、IFN-r及小腸細胞凋亡的增加。此外，麩醯胺酸顯著降低小腸NO及血漿精胺酸的濃度，並增加肌肉層厚度；補充精胺酸顯著改善小腸腺窩深度的降低並減少小腸核內NF-kB比值；而補充瓜胺酸顯著減緩小腸腺窩深度的降低並減少小腸核內NF-kB比值，但降低小腸腺窩細胞增生。本研究結果證實，小腸缺血再灌流3小時造成小腸黏膜受損，且引發全身性蛋白質異化作用及發炎反應；而小腸缺血再灌流24小時後，引發小腸受損情形較不明顯，但可藉由全身性發炎反應影響肝臟及腎臟功能的改變。口服補充瓜胺酸具有改善小腸缺血再灌流引發之早期小腸損傷的作用，且補充麩醯胺酸、精胺酸及瓜胺酸皆有減緩小腸缺血再灌流引發之早期及後期腸道細胞凋亡及發炎反應的作用。

Intestinal ischemia and reperfusion (I/R) commonly results in systemic inflammation and multiple organs failure and further leads to death. The results of animal studies demonstrated that administration of glutamine and arginine prior to ischemia may increase the survival rate of animals after reperfusion, and may enhance the repair of intestinal mucosa. However, these beneficial effects were not found in post-ischemia and reperfusion supplementation in clinical practice. In addition, several studies indicated that supplementation citrulline may increase de novo arginine synthesis without overproduction of nitric oxide (NO). However, there was limited evidence. Therefore, using ischemic rats to mimic the intestinal I/R-induced acute and chronic injury in clinical situations, we compared the effects of pre-reperfusion and post-reperfusion administration of orogastric glutamine, arginine, and citrulline on improving the intestinal I/R-induced intestinal injury. Male Wistar rats were divided into nine groups, that is, one normal control group and eight intestinal I/R groups which underwent occlusion of superior mesenteric artery for 60 min with 3 or 24 hours of reperfusion before the execution. Fifteen minutes before and 3, 9 and 21 hours after the reperfusion, animals were supplemented with placebo, glutamine, arginine, or citrulline. Our results showed that after 3 and 24 hours of reperfusion, rats had significantly increased plasma concentrations of NO, interleukin (IL)-6 and interferon (IFN)-r. Rats with 3 hour reperfusion had significantly increased plasma glutamine, citrulline arginine and tumor necrosis factor (TNF)-a and jejunal citrulline content, apoptotic index, myeloperoxidase (MPO) activity and neuronal nitric oxide synthase (nNOS) protein expression, as well as had significantly decreased jejunal histology and mass, crypt depth and nuclear transcriptional factor (NF)-kB ratio compared to normal rats. When rats suffered with 24 hour reperfusion, the liver weight, serum albumin, biomarkers of hepatic and renal function and white blood cell counts were significantly increased, whereas jejunal TNF-a, IL-6 contents and nNOS protein expression were significantly decreased. Supplementation of glutamine, arginine and citrulline significantly attenuated the increases in jejunal apoptotic index, nNOS protein expression and 3 hour reperfusion-induced increase in plasma IL-6. In ischemic rats with 3 hour reperfusion, glutamine supplementation significantly decreased plasma TNF-a and mucosal protein in the jejunum. Arginine supplementation significantly improved the decreases in jejunal crypt depth and muscularis thickness, whereas significantly decreased the crypt cell proliferation. In addition, citrulline supplementation significantly improved the decreases in jejunal histology and mass and attenuated the increases in plasma glutamine, NO TNF-a and jejunal MPO activity. In ischemic rats with 24 hour reperfusion, glutamine, arginine and citrulline supplementations significantly attenuated the increases in plasma NO, IFN-r and jejunal apoptotic index. Moreover, glutamine supplementation significantly decreased the jejunal NO and plasma arginine and increased jejunal muscularis thickness. Arginine supplementation significantly improved the decrease in jejunal crypt depth, and significantly decreased jejunal NF-kB ratio. And, citrulline supplementation significantly attenuated the decrease in jejunal crypt depth and significantly decreased jejunal NF-kB ratio, whereas significantly decreased the cell proliferation of jejunal crypt. The results of the present study demonstrated that intestinal ischemia and 3 hour reperfusion could cause intestinal mucosal damage and systemic protein catabolism and inflammation; and 24 hour reperfusion could not cause significant jejunal damage, but the hepatic and renal function could affected via the systemic inflammatory response. In addition, orogastric administration of citrulline supplementation significantly attenuates intestinal I/R-induced intestinal damage in early stage and glutamine, arginine and citrulline supplementation significantly alleviate jejunal apoptosis and systemic inflammatory response after early and late stage.

TABLE OF CONTENT

ABSTRACT IN CHINESE............................................................ii
ABSTRACT IN ENGLISH............................................................iv
ACKNOWLEDGEMENTS...............................................................vii
LIST OF TABLES.................................................................xiv
LIST OF FIGURES................................................................xv
ABBREVIATION...................................................................xvii

CHAPTER 1 INTRODUCTION.........................................................1

CHAPTER 2 LITERATURE REVIEW....................................................3
Ⅰ. Small intestine........................................................3
A. The structure of small intestine....................................3
1. Mucosa......................................................3
2. Submucosa...................................................4
3. Muscularis..................................................4
4. Serosa......................................................5
B. The physiological functions of small intestine......................5
1. Digestion...................................................5
2. Absorption..................................................6
3. Barrier function............................................7
C. Small intestinal disorders..........................................8
Ⅱ. Intestinal ischemia and reperfusion (I/R)..............................10
A. Clinical relevance..................................................10
B. Intestinal ischemia.................................................11
1. Intestinal mesenteric blood flow............................11
2. The pathophysiology of intestinal ischemia..................12
a. Arterial embolism...................................13
b. Arterial thrombosis.................................13
c. Mesenteric venous thrombosis........................14
d. Nonocclusive mesenteric ischemia....................14
C. Reperfusion.........................................14
1. Reactive oxygen species (ROS)...............................15
2. Polymorphonuclear neutrophils (PMS).........................16
3. Local damages and inflammatory response.....................18
a. Intestinal mass and morphology......................18
b. Proinflammatory cytokines...........................20
c. Nitric oxide (NO)...................................20
d. Nuclear factor-kB (NF-kB) and I-kB..................21
e. Enterocyte apoptosis................................22
f. Crypt cell proliferation............................23
4. Remote organ failure........................................24
a. Lung injury.........................................24
b. Liver injury........................................25
c. Kidney injury.......................................25
5. Metabolic responses.........................................26
6. Therapeutics................................................27
a. Pharmacological treatments..........................27
b. Surgery.............................................27
c. Alternative treatments..............................28
Ⅲ. Amino acid supplementation.................................................30
A. Glutamine...........................................................30
1. The role of physiology......................................30
2. Therapeutic implications....................................31
B. Arginine............................................................31
1. The role of physiology......................................31
2. Therapeutic implications....................................32
C. Citrulline.........................................................34
1. The role of physiology......................................34
2. Therapeutic implications....................................35
D. Amino acid interorgan metabolism...................................36

CHAPTER 3 AIMS AND HYPOTHESIS..................................................39

CHAPTER 4 MATERIALS AND METHODS................................................41
Ⅰ. Animals and experimental design............................................41
Ⅱ. Analytic measurements......................................................46
A. Serological analysis................................................46
B. Amino acid levels in the plasma and jejunum.........................46
C. Inflammatory response in the plasma and jejunum.....................47
D. Jejunal morphology..................................................48
E. Jejunal mass........................................................48
F. Jejunal apoptotic index.............................................48
G. Jejunal myeloperoxidase activity....................................49
H. Jejunal pNF-kB, NF-kB, I-kB and NOS expression......................50
I. Crypt cell proliferation index......................................51
Ⅲ. Statistical analysis.......................................................51

CHAPTER 5 RESULTS..............................................................52
Ⅰ. Body weight and weights of organs and tissues..............................52
Ⅱ. Blood and serum substrate concentrations...................................52
Ⅲ. Amino acid profiles in the plasma and jejunum..............................53
Ⅳ. Inflammatory mediators in the plasma and jejunum...........................54
Ⅴ. Composition and architecture of the jejunum................................55
Ⅵ. Jejunal villus apoptosis...................................................56
Ⅶ. Jejunal myeloperoxidase activity...........................................57
Ⅷ. Expression of NF-kB, I-kB and NOS in the jejunum...........................57
Ⅸ. Crypt cell proliferation of the jejunum....................................58

CHAPTER 6 DISCUSSION...........................................................94

CHAPTER 7 CONCLUSIONS..........................................................96

CHAPTER 8 REFERENCES...........................................................98

APPENDICES
APPENDIXⅠ. Anti-body dilute folds for western blotting........................118
APPENDIXⅡ. Oral presentation in TSPEN 2009....................................119
APPENDIXⅢ. Oral presentation in TSPEN 2010....................................123
APPENDIXⅣ. Poster presentation in AFLAS 2010..................................127
APPENDIXⅤ. Oral presentation in TSPEN 2011....................................132
APPENDIXⅥ. Manuscript in press................................................136


LIST OF TABLES

Table 1. Weights of organs and tissues.........................................59
Table 2. The numbers of complete blood count...................................60
Table 3. Serum substrate concentrations........................................61
Table 4. Plasma concentrations of arginine metabolism-
associated amino acids................................................62
Table 5. Jejunal content of arginine metabolism-
associated amino acids................................................63
Table 6. Plasma concentrations of nitric oxide and
cytokines.............................................................64
Table 7. Jejunal contents of nitric oxide and cytokines........................65

LIST OF FIGURES

Figure 1. Cross-section and small-structure of the small intestine
showing the tissue layers, plicae circulares, and villi..............9
Figure 2. The emigration of PMNs from the postcapillary venules
to areas of Inflammation.............................................17
Figure 3. The clinical features of acute mesenteric ischemia...................19
Figure 4. Overview of mammalian arginine-associated amino acids
Metabolism...........................................................33
Figure 5. Metabolism of amino acid interorgan pathway..........................38
Figure 6. The anatomy and morphological changes of the small intestine
with 0 to 60 minutes of superior mesenteric artery occlusion.........44
Figure 7. Experimental scheme of intestinal ischemia and reperfusion...........45
Figure 8. Body weights.........................................................66
Figure 9. Light micrographs of the jejunum stained with hemotoxylin and
eosin in normal and intestinal I/R rats with 3 hours of reperfusion..67
Figure 10.Light micrographs of the jejunum stained with hemotoxylin and
eosin in normal and intestinal I/R rats with 24 hours of reperfusion.68
Figure 11.Villus height of the jejunum.........................................69
Figure 12.Crypt depth of the jejunum...........................................70
Figure 13.Muscularis thickness of the jejunum..................................71
Figure 14.Wet weights of the jejunal mucosa....................................72
Figure 15.Dry weights of the jejunal mucosa....................................73
Figure 16.Protein content of the jejunal mucosa................................74
Figure 17.DNA content of the jejunal mucosa....................................75
Figure 18.Wet weights of jejunal muscularis....................................76
Figure 19.Dry weights of jejunal muscularis....................................77
Figure 20.Protein content of jejunal muscularis................................78
Figure 21.DNA content of jejunal muscularis....................................79
Figure 22.Fluorescent micrographs of the jejunal apoptosis stained with TUNEL
in normal and intestinal I/R rats with 3 hours of reperfusion........80
Figure 23.Fluorescent micrographs of the jejunal apoptosis stained with TUNEL
in normal and intestinal I/R rats with 24 hours of reperfusion.......81
Figure 24.The apoptotic index of the jejunum...................................82
Figure 25.Myeloperoxidase activity of the jejunum..............................83
Figure 26.Protein expression of phosphorylated nuclear factor-kB (NF-kB).......84
Figure 27.Protein expression of nuclear factor-kB (NF-kB)......................85
Figure 28.pNF-kB/NF-kB ratio in the jejunum....................................86
Figure 29.Protein expression of I-kB in the jejunum............................87
Figure 30.Protein expression of iNOS in the jejunum............................88
Figure 31.Protein expression of eNOS in the jejunum............................89
Figure 32.Protein expression of nNOS in the jejunum............................90
Figure 33.Fluorescent micrographs of cell proliferation in the jejunum
stained with BrdU in normal and intestinal I/R rats with 3 hours
of reperfusion.......................................................91
Figure 34.Fluorescent micrographs of cell proliferation in the jejunum
stained with BrdU in normal and intestinal I/R rats with 24 hours
of reperfusion.......................................................92
Figure 35.The proliferation index of the jejunum...............................93

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