跳到主要內容

臺灣博碩士論文加值系統

(44.200.77.92) 您好!臺灣時間:2024/03/01 09:29
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:傅仁煇
研究生(外文):Ren Huei Fu
論文名稱:早產兒紅血球抗氧化機制及抗氧化能力與早產兒慢性肺病相關性之研究
論文名稱(外文):The Erythrocyte Antioxienzyme Activity in Preteerm Infants and the Correlation with the Development of Bronchopulmonary Dysplasia.
指導教授:郭敏玲郭敏玲引用關係
指導教授(外文):M. L. Kuo
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
論文頁數:121
中文關鍵詞:早產兒慢性肺病抗氧化酵素高氧肺動脈血管內皮細胞
外文關鍵詞:Bronchopulmonary dysplasiaantioxyenzymehyperoxiapulmonary artery endothelial cell
相關次數:
  • 被引用被引用:0
  • 點閱點閱:317
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
早產兒慢性肺病(BPD)為多危險因子之早產兒疾病,同時也是早產兒疾病中與氧氣自由基傷害有關的疾病之一。關於氧氣自由基傷害的形成目前有兩種假說;其一為自由基的過度生成或氧化損傷,其二為酵素或非酵素性之抗氧化能力不足。若抗氧化能力不足與早產兒慢性肺病的形成相關,應該在出生後初期即可偵測得到。目前文獻中較少有關於早產兒抗氧化能力之報告,或抗氧化能力與慢性肺病之相關性研究。由於早產兒肺部檢體取得不易,我們採紅血球做為檢體。我們假設過多的自由基由肺泡擴散至血液中時,紅血球將是抗氧化防禦的第一線,因此紅血球的抗氧化能力有其重要性。另外我們亦使用胎羊肺動脈血管內皮細胞進行高氧下細胞培養之研究,希望能夠建立一個細胞培養之高氧模式,可作為細胞學上觀察慢性肺病可能之反應。
結果顯示有慢性肺病者其出生週數與體重皆較小,但抗氧化酵素之活性與週數及體重無相關性,有慢性肺病者出生後第5天其累計氧氣使用量較高,在其他臨床數據無顯著差異的情況下,紅血球SOD活性在第5天亦上升,CAT活性無差異,而c-GPx活性則明顯較低。由GSH/GSSG比例上升亦證明此現象,顯示其可能有較高之氧化損傷。而較低之c-GPx活性可能在慢性肺病形成上佔有其角色,也由此可推斷GSH在體內的循環機制與疾病之相關性仍須再評估。在細胞培養方面,肺動脈血管內皮細胞培養於高氧環境之結果,與預期中慢性肺病之細胞病理學上之反應相似,由此一模式證明高氧抑制肺動脈血管內皮細胞生長與血管生成之功能,但須要再進行其他肺部細胞與抗氧化能力之相關實驗,但為一可行之細胞高氧模式。
Bronchopulmonary dysplasia (BPD), or chronic lung disease of prematurity is a disease of multiple risk factors. However, BPD is also one of several diseases of preterm infants considered to correlate with oxygen free radical injury. Two hypotheses have been proposed about the causes of injury. One is over production of free radicals or excess oxidative stress. The other one is the deficiency of antioxidant defense mechanisms, including enzymatic and non-enzymatic systems. If deficiency of antioxidant defense mechanism plays a role in the development of BPD, it should be detected early in the post-natal life. There were no clear document about the antioxidant defense ability of preterm infants and the correlations between the ability and the development of BPD. Due to the difficulty in collecting the pulmonary tissue from preterm infants, we decided to use red blood cells (RBC) as our specimens. We think that if the oxygen free radicals diffuse from the alveolar into the blood stream, RBCs will be the first in line to manage the free radicals. In order to study the cellular response under hyperoxic conditions, we used fetal sheep pulmonary artery endothelial cells and cultured them under hyperoxic condition to establish a cellular model. Further evaluation of the results of these cells may help us understand more about the cellular change in BPD.
Our aims are to measure the antioxidant defense ability, and to evaluate the correlations between the ability and the development of BPD. Therefore, we measure the antioxyenzyme activity and some antioxidants in RBC of pretem infants with and without BPD. Further study on cell culture is to evaluate the antioxyenzyme activities in cells under hyperoxic conditions. Higher cumulative oxygen doses on day 5 might indicate increased oxidative stress in BPD group. This could be the cause of elevation of erythrocyte SOD activity. Erythrocyte c-GPx activity was lower in BPD group on day 5. This result was supported by the elevation of erythrocyte GSH/GSSG ratio. These data showed that c-GPx could be the key enzyme in the development of BPD. They also indicated that further evaluation of glutathione recycling system is important to the research of BPD. With the cell culture model, the results proved that hyperoxia would suppress the cell growth, tube formation, and some antioxyenzyme activities. It also changed the cell cycle distribution and increase apoptosis percentage. However, the model appeared to be an available model for hyperoxic condition.
指導教授推薦書
口試委員審定書
授權書…………………………………………………………………iii
致謝……………………………………………………………………iv
ABBREVIATIONS…………………………………………………...v
摘要(中文) …………………………………………………………vii
ABSTRACT (English)………………………………………………ix
TABLE OF CONTENTS……………………………………………xi
Chapter I Introduction…………………………………………1
I-1 Free radicals…………………………………………………1
I-1-a Production of free radicals in cells……………2
I-1-b Damage reaction of free radicals……………………3
I-1-c Free radical disorders of preterm infants……4
I-2 Oxygen free radical/antioxidant imbalance theories..5
I-2-a Excess oxygen and lung injury……………………………5
I-2-b Hypoxia-reoxygenation and endothelial cell injury…6
I-3 Bronchopulmonary dysplasia (BPD)………………………7
I-3-a Historical overview………………………………………7
I-3-b Definition of BPD………………………………………8
I-3-c Epidemiology……………………………………………8
I-3-d Pathobiology and pathogenesis…………………………9
I-3-e Etiologic factors……………………………………………9
I-3-f Oxygen toxicity in BPD……………………………………9
I-3-g Evidence of oxidative damage in BPD……………………10
I-4 Antioxidant defense……………………………………………11
I-4-a Enzymatic and nonenzymatic antioxidant defense mechanism………12
I-4-b Antioxyenzymes in erythrocyte………………………12
I-4-c Other correlated enzymes or antioxidants………15
I-5 Pulmonary cells under various hyperoxia conditions…17
I-5-a Pulmonary alveolar epithelial cells (PAEpiC)………18
I-5-b Pulmonary artery endothelial cells (PAEC)…………18
I-5-c Pulmonary artery smooth muscle cells (PASMC)…19
I-5-d Hyperoxic culture conditions…………………………19
Chapter II Hypotheses and Aims of Study…………………21
II-1 The antioxyenzyme activities and BPD………………21
II-2 The in vitro cell culture model………………………22
Chapter III Materials and Methods…………………………23
III-1 Materials for antioxyenzyme activity………………23
III-2 Methods and criteria of patient data collection…23
III-2-a Diagnosis of BPD………………………………………23
III-2-b Assisted ventilation and oxygen administration policy..24
III-2-c Criteria for blood transfusion…………………24
III-2-d Diagnosis of other associated diseases………24
III-2-e Other clinical data……………………………………25
III-3 Mathods for samples management………………………25
III-3-a Blood sample collection……………………………25
III-3-b SOD activity……………………………………………25
III-3-c CAT activity……………………………………………28
III-3-d Cellular GPx activity………………………………29
III-3-e GSH and GSSG…………………………………………30
III-4 Materials of in vitro cell culture model………33
III-5 Methods for cell culture model………………………34
III-6 Statistical analyses……………………………………36
Chapter IV Results…………………………………………………38
IV-1 Erythrocyte antioxyenzyme activities and preterm infants with and without BPD…………………………………38
IV-1-a Patients…………………………………………………38
IV-1-b Correction of data…………………………………38
IV-1-c Correlations between enzyme activities and GA or BW..38
IV-1-d Red blood cell transfusion and antioxyenzyme activities………………………………………………………39
IV-1-e Erythrocyte antioxyenzyme activities…………41
IV-1-f Erythrocyte GSH/GSSG ratios………………………41
IV-1-g Cumulative oxygen administration…………………41
IV-1-h Types of assisted ventilation and the number of patients…………………………………………………42
IV-1-i Nutritional statuses of the preterm infants…42
IV-1-j Other clinical conditions……………………………43
IV-2 Erythrocyte antioxyenzyme activities and preterm infants with and without ROP…………………………………44
IV-2-a Patients…………………………………………………44
IV-2-b Erythrocyte antioxyenzyme activities and ROP…45
IV-2-c Cumulative oxygen administration…………………45
IV-3 Hyperoxic exposure of PAECs……………………………45
Chapter V Discussion………………………………………………47
V-1 Erythrocyte SOD activity in preterm infants………47
V-2 Erythrocyte CAT, c-GPx activities in preterm infants…51
V-3 Erythrocyte GSH/GSSG ratios in preterm infants……55
V-4 ROP and erythrocyte antioxyenzyme activity…………56
V-5 PAECs cultured under various hyperoxic conditions……59
Chapter VI Conclusions…………………………………………61
VI-1 Erythrocyte antioxyenzyme activities of preterm infants..61
VI-2 PAECs cultured under various hyperoxic conditions…62
REFERENCES…………………………………………………63
TABLES………………………………………………………73
FIGURES……………………………………………………78
APPENDIX……………………………………………………103
REFERENCES
1. Cheeseman KH, Slater TF: An introduction to free radical biochemistry. Br Med Bull 1993; 49: 481-493.
2. Holley AE, Cheeseman KH: Measuring free radical reactions in vivo. Br Med Bull 1993; 49: 494-505.
3. Kelly FJ: Free radical disorders of preterm infants. Br Med Bull 1993; 49: 668-678.
4. Gerschman R, Gilbert DL, Nye SW, Dwyer P, Fenn WO. Oxygen poisoning and X-radiation: a mechanism in common. Science 1954; 119: 623-626.
5. McCord JM, Fridovich I. Superoxide dismutase, an enzymic function for erythrocuprein (hemocuprein). J Biol Chem 1969; 244: 6049 - 6055.
6. Banks-Randall BA, Ballard RA: Bronchopulmonary dysplasia. In: Taeusch HW, Ballard RA, Gleason CA: Avery’s diseases of the newborn. 8th ed. Elsevier Saunders, PA, USA. 2004; 723-736.
7. Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163: 1723-1729.
8. Saugstad OD: Mechanisms of tissue injury by oxygen radicals: implications for neonatal disease. Acta Paediatr 1996; 85: 1-4.
9. Saugstad OD. Bronchopulmonary dysplasia and oxidative stress: are we closer to an understanding of the pathogenesis of BPD? Acta Paediatr 1997; 86: 1277-1282.
10. Saugstad OD. Bronchopulmonary dysplasia-oxidative stress and antioxidants. Semin Neonatal 2003; 8: 39-49.
11. Gandlish JK, Tho LL, Lee HW: Erythrocyte enzymes decomposing reactive oxygen species and gestational age. Early Hum Dev 1995; 43: 145-150.
12. Phylactos AC, Leaf AA, Costeloe K, Crawford MA: Erythrocyte cupric/zinc superoxide dismutase exhibits reduced activity in preterm and low-birth weight infants at birth. Acta Paediatr 1995; 84: 1421-1425.
13. Ripalda MJ, Rudolph N, Wong SL: Developmental patterns of antioxidant defense mechanisms in human erythrocytes. Pediatr Res 1989; 26: 366-369.
14. Aliakbar S, Brown PR, Bidwell D, Nicolaides KH: Human erythrocyte superoxide dismutase in adults, neonates, and normal, hypoxaemic, anaemic, and chromosomally abnormal fetuses. Clin Biochem 1993; 26: 109-115.
15. Soave MC, Moulsma M, Chevalier P, Pillot R, Guidollet J: Increased superoxide dismutase activity in erythrocytes of children with pulmonary hypertension. Clin Chim Acta 1992; 209: 95-101.
16. Jobe AJ: The new BPD: an arrest of lung development. Pediatr Res 1999; 46: 641-643.
17. Coalson JJ: Pathology of new bronchopulmonary dysplasia. Semin Neonatol 2003; 8: 73-81.
18. Bancalari E, Claure N, Sosenko IR: Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology, and definition. Semin Neonatol 2003; 8: 63-71.
19. Lin YJ, Markham NE, Balasubramaniam V, Tang JR, Maxey A, Kinsella JP, Abman SH: Inhaled nitric oxide enhances distal lung growth after exposure to hyperoxia in neonatal rats. Pediatr Res 2005; 58: 22-29.
20. Wright JR, Dobbs LG: Regulation of pulmonary surfactant secretion and clearance. Annu Rev Physiol 1991; 53: 395-414.
21. Wilson CN, Batra VK: Lipopolysaccharide bind to and activates A(1) adenosine receptors on human pulmonary artery endothelial cells. J Endotoxin Res 2002; 8: 263-271.
22. Schwartz SM, Campbell GR, Campbell JH: Replication of smooth muscle cells in vascular disease. Circ Res 1986; 58: 427-444.
23. Fan QI, Vanderpool K, Marsh JD: A 27 bp cis-acting sequence is essential for L-type calcium channel alpha (1C) subunit expression in vascular smooth muscle cells. Biochim Biophys Acta 2002; 1577: 401-411.
24. Braun M, Pietsch P, Schror K, Baumann G, Felix SB: Cellular adhesion molecules on vascular smooth muscle cells. Cardiovasc Res 1999; 41: 395-401.
25. Quinn TP, Schlueter M, Soifer SJ, Gutierrez JA: Cyclic mechanical stretch induces VEGF and FGF-2 expression in pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2002; 282: L897-903.
26. Rose F, et al. Hypoxic pulmonary artery fibroblasts trigger proliferation of vascular smooth muscle cells: role of hypoxia-inducible transcription factors. FASEB J 2002; 12: 1660-1661.
27. Tietze F: Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 1969; 27: 502-522.
28. Nebot C, Moutet M, Huet P, Xu JZ, Yadan JC, Chaudiere J: Spectrophotometric assay of superoxide dismutase activity based on the activated autoxidation of a tetracyclic catechol. Anal Biochem 1993; 214: 442-451.
29. Cooke RWI, Drury JA, Yoxall CW, James C: Blood transfusions and chronic lung disease in preterm infants. Eur J Pediatr 1997; 156: 47-50.
30. Silvers KM, Gibson AT, Russell JM, Powers HJ: Antioxidant activity, packed cell transfusions, and outcome in preture infants. Arch Dis Child Fetal Neonatal Ed 1998; 78: F214-F219.
31. Hirano K, Morinobu T, Kim H, Hiroi M, Ban R, Ogawa S, Ogihara H, Tamai H, Ogihara T: Blood transfusion increases radical promoting non-transferrin bound iron in preterm infants. Arch Dis Child Fetal Neonatal Ed 2001; 84: F188-F193.
32. Wardle SP, Drury J, Garr R, Weindling AM: Effect of blood transfusion on lipid peroxidation in preterm infants. Arch Dis Child Fetal Neonatal Ed 2002; 86: F46-F48.
33. Bonta BW, Gawron ER, Warshaw JB: Neonatal red cell superxide dismutase enzyme levels: possible role as a cellular defense mechanism against pulmonary oxygen toxicity. Pediat Res 1977; 11: 754-757.
34. Davis JM, Parad RB, Michele T, Allred E, Price A, Rosenfeld W: Pulmonary outcome at 1 year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics 2003; 111: 469-476.
35. Liochev SI, Fridovich I: Copper, zinc superoxide dismutase and H2O2: effects of biocarbonate on inactivationand oxidation of NADPH and urate, and on consumption of H2O2. J Biol Chem 2002; 277: 34674-34678.
36. Liochev SI, Fridovich I: On the role of bicarbonate in peroxidations catalyzed by Cu, Zn superoxide dismutase. Free Radic Biol Med 1999; 27: 1444-1447.
37. de Haan JB, Cristiano F, Iannello RC, Kola I: Cu/Zn-superoxide dismutase and glutathione peroxidase during aging. Biochem Mol Biol Int 1995; 35: 1281-1297.
38. Georgeson GD, Szöny BJ, Streitman K, Varga IS, Kovács A, Kovács L: Antioxidant enzyme activities are decreased in preterm infants and in neonatesborn via caesarean section. Eur J Obstet Gynecol Reprod Biol 2002; 103: 136-139.
39. Ochoa JJ, Ramirez-Tortosa MC, Quiles JL, Palomino N, Robles R, Mataix J, Huertas JR: Oxidative stress in erythrocytes from premature and full-term infants during their first 72h of life. Free Radic Res 2003; 37: 317-322.
40. Agostoni A, Gerli GC, Beretta L, Bianchi M, Vignali M, Bombelli F: Superoxide dismutase, catalase and glutathione peroxidase activities in maternal and cord blood erythrocytes. J Clin Chem Clin Biochem 1980; 18: 771-773.
41. Frosali S, Di Simplicio P, Perrone S, Di Giuseppe D, Longini M, Tanganelli D, Buonocore G: Glutathione recycling and antioxidant enzyme activities in erythrocytes of term and preterm newborns at birth. Biol Neonate 2004; 85: 188-194.
42. Candlish JK, Tho LL, HW Lee: Erythrocyte enzymes decomposing reactive oxygen species and gestational age. Early Hum Dev 1995; 43: 145-150.
43. Varga SJ, Matkovics B, Pataki L, Molnár A, Novák Z: Comparison of antioxidant red blood cell enzymes in premature and full-term neonates. Clin Chim Acta 1985; 147: 191-195.
44. Zima T, Štípek S, Crkovská J, Doudová D, Měchurová A, Calda P: Activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase in fetal erythrocytes. Prenat Diagn 1996; 16: 1083-1085.
45. Fu RH, Yang PH, Chiang MC, Chiang CC, Cho YH, Chou YH: Erythrocyte Cu/Zn superoxide dismutase activity in preterm infants with and without bronchopulmonary dysplasia. Biol Neonate 2005; 88: 35-41.
46. Wilson DC, Tubman TRJ, Bell N, Halliday HL, McMaster D: Effect of blood transfusion on plasma selenium, glutathione peroxidase and manganese levels in very low birth weight infants. Biol Neonate 1991; 60: 148-151.
47. Pleban PA, Munyani A and J Beachum: Determination of selenium concentration and glutathione peroxidase activity in plasma and erythrocytes. Clin Chem 1982; 28: 311-316.
48. Darlow BA, Inder TE, Graham PJ, Sluis KB, Malpas TJ, Taylor BJ, Winterbourn CC: The relationship of selenium status to respiratory outcome in the very low birth weight infant. Pediatrics 1995; 96: 314-319.
49. Daniels LA, Gibson RA, Simmer K: Glutathione peroxidase is not a functional marker of selenium status in the neonatal period. J Pediatr Gastroenterol Nutr 1998; 26: 263-268.
50. Mentro AM, Smith AM, Moyer-Mileur L: Plasma and erythrocyte selenium and glutathione peroxidase activity in preterm infants at risk for bronchopulmonary dysplasia. Biol Trace Elem Res 2005; 106: 97-106.
51. Tubman TR, Halliday HL, McMaster D: Glutathione peroxidase and selenium levels in the preterm infant. Biol Neonate 1990; 58: 305-310.
52. Burdon RH: Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 1995; 18: 775-794.
53. Sandberg K, Fellman V, Stigson L, Thiringer K, Hjalmarson O: N-acetylcysteine administration during the first week of life does not improve lung function in extremely low birth weight infants. Biol Neonate 2004; 86: 275-279.
54. Kim TI, Sohn J, Pi SY, Yoon YH: Postnatal risk factors of retinopathy of prematurity. Paediatr Perinat Ep 2004; 18: 130-134.
55. Lin HJ, Lin CC, Tsai SW, Lin HC, Su BH: Risk factors for retinopathy of prematurity in very low birth-weight infants. J Chin Med Assoc 2003; 66: 662-668.
56. Mccolm JR, Fleck BW: Retinopathy of prematurity: causation. Semin Neonatolo 2001; 6: 453-460.
57. Karna P, Muttineni J, Angell L, Karmaus W: Retinopathy of prematurity and risk factors: a prospective cohort study. BMC Pediatrics 2005; 5: 18.
58. Wheatley CM, Dickinson JL, Mackey DA, Craig JE, Sale MM: Retinopathy of prematurity: recent advances in our understanding. Arch. Dis. Child. Fetal Neonatal. Ed. 2002; 87: 78-82.
59. York JR, Landers S, Kirby RS, Arbogast PG, Penn JS: Arterial oxygen fluctuation and retinopathy of prematurity in very-low-birth-weight infants. J Perinatol 2004; 24: 82-87.
60. Cunningham S, Fleck BW, Elton RA, McIntosh N: Transcutaneous oxygen levels in retinopathy of prematurity. Lancet 1995; 346 (8988): 1464-1465.
61. Saito Y, Omoto T, Cho Y, Hatsukawa Y, Fujimura M, Takeuchi T: The progression of retinopathy of prematurity and fluctuation in blood gas tension. Graefe’s Arch. Clin Exp Ophthalmol 1993; 231: 151-156.
62. Saugstad OD: Update on oxygen radical disease in neonatology. Curr Opin Obstet Gynecol 2001; 13: 147-153.
63. Saugstad OD: Oxygen and retinopathy of prematuriy. J Perinatol 2006; 26: S46-S50.
64. Askie L: Appropriate levels of oxygen saturation for preterm infants. Acta Paediatr Suppl 2004; 444: 26-28.
65. McGregor ML, Bremer DL, Cole C, McClead RE, Phelps DL, Fellows RR, Oden N: Retinopathy of prematurity outcome in infants with prethreshold retinopathy of prematurity and oxygen saturation >94% in room air: the high oxygen percentage in retinopathy of prematurity study. Pediatrics 2002; 110: 540-544.
66. Smith LE: Pathogenesis of retinopathy of prematurity. Acta Paediatr Suppl 2002; 437: 26-28.
67. Smith LE: Pathogenesis of retinopathy of prematurity. Semin Neonatol 2003; 8: 469-473.
68. Papp A, Németh I, Karg E, Papp E: Glutathione status in retinopathy of prematurity. Free Radic Biol Med 1999; 27: 738-743.
69. Lubetzky R, Stolovitch C, Dollberg S, Minouni FB, Salomon M, Mandel D: Nucleated red blood cells in preterm infants with retinopathy of prematurity. Pediatrics 2005; 116: e619-e6622.
70. Zhang R, Wang L, Zhang L, Chen J, Zhu Z, Zhang Z, Chopp M. Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 2003; 92: 308-313.
71. Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, Walsh MC, Durand DJ, Mayock DE, Eichenwald EC, Null DR, Hudak ML, Puri AR, Golombek SG, Courtney SE, Stewart DL, Welty SE, Phibbs RH, Hibbs AM, Luan X, Wadlinger SR, Asselin JM, Coburn CE. Inhaled Nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 2006; 355: 343-353.
72. Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, Sekar KC, Auten RL, Bhutani VK, Gerdes JS, George TN, Southgate WM, Carriedo H, Couser RJ, Mammel MC, Hall DC, Pappagallo M, Sardesai S, Strain JD, Baier M, Abman SH. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 2006; 355: 354-364.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top