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| 研究生： |
李宜哲 Lee, Yi-Jer |
|---|---|
| 論文名稱： |
腹膜透析液留置時間對於透析時發生腹膜上皮細胞間質轉化的影響 The effect of dwelling time on epithelial-to-mesenchymal transition of mesothelial cells during peritoneal dialysis |
| 指導教授： |
邱元佑
Chiou, Yuan-Yow 蔡曜聲 Tsai, Yau-Sheng |
| 學位類別： |
碩士 Master |
| 系所名稱： |
醫學院 - 臨床醫學研究所 Institute of Clinical Medicine |
| 論文出版年： | 2011 |
| 畢業學年度： | 99 |
| 語文別： | 英文 |
| 論文頁數： | 81 |
| 中文關鍵詞： | 腹膜透析 、留置時間 、上皮細胞間質轉化 |
| 外文關鍵詞： | dwelling time, epithelial-to-mesenchymal transition, peritoneal dialysis |
| 相關次數： | 點閱：72 下載：1 |
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腹膜透析的治療是血液透析外之另一種腎臟替代療法，其效果及預後已證實和血液透析相等，且有其獨特而優於血液透析的長處。但此種治療之最重要問題就是病人在接受一段時間的腹膜透析治療後，其腹膜細胞的形態與功能會產生變化且最終會導致腹膜透析治療的失敗。此種現象目前被歸因於長期暴露在傳統非生理性的透析液以及腹膜炎或腹腔積血等等所導致的急慢性發炎反應。在病理機制上，腹膜透析治療所引起腹膜細胞發生上皮細胞間質轉化現象被認為是後續引起腹膜形態以及功能變化的一個非常重要的原因。直至今日為止，臨床上到底有哪些原因會促進腹膜細胞發生上皮細胞間質轉化則仍未有定論。本實驗旨在透過臨床病人的透析引流液內之腹膜上皮細胞培養來判斷病人體內腹膜細胞的變化，並與臨床相關因素分析比對，進而分析探討影響腹膜細胞發生上皮細胞間質轉化的相關因子。在實驗過程中總共收集了53個病人的透析引流液內之腹膜上皮細胞，結果顯示47%的病人的腹膜上皮細胞已發生上皮細胞間質轉化，28％的病人尚未發生，而有15％的患者是介於兩者之間。與臨床相關因素之分析中，經多重邏輯回歸分析後，只有留置時間之長短是統計學上顯著的獨立危險因子，意即不間斷透析治療的病人(每天留置時間達24小時) 發生上皮細胞間質轉化的機率會顯著提高。此外，於細胞實驗中也證實了持續暴露於非生理特性的透析液較易發生上皮細胞間質轉化。但透過合併使用符合生理特性的腹膜透析液，則可能可以緩解此現象發生。總之，於吾人的研究中我們證實了腹膜透析液留置時間為影響腹膜細胞上皮細胞間質轉化的一個非常重要因素。但透過使用符合生理特性的腹膜透析液，則可能可以有效減緩上皮細胞間質轉化的發生。
Peritoneal dialysis (PD) therapy is well known to induce morphological and functional alterations in peritoneal membrance. Long term exposure to conventional non-physiologic dialysate and peritonitis or hemoperitoneum are the main causes of acute/chronic inflammation. Consequently, peritoneal membrane (PM) undergoes structure change including angiogenesis, fibrosis, and hyalinizing vasculopathy and contributed to technique failure finally. Epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MCs) also play an important role in peritoneal membrane dysfunction during PD therapy, but the mechanism is still obscure. To test the mechanism of MCs EMT change on PD therapy, 53 clinical stable PD patients were enrolled in this study to investigate the parameter which can impact on EMT. EMT assessments through human peritoneal MCs were cultured from dialysate effluent. Forty seven percent of patients presented EMT phenomenon, 28 % of patients present non-EMT and 15% of patients were classified as mixed group. Patients who received persist PD therapy (dwelling time 24hrs per day) showed significantly higher EMT change. After multiple logistic regression, dwelling time still showed as a significant independent factor to predict EMT. In in vitro study, human peritoneal MCs which persist exposure to conventional high glucose degradation products (GDPs) base dialysate showed more EMT tendency, and it may be alleviated by more bio-compatible dialysate. In our study, we provide the evidence that dwelling time has significant effect on the occurrence of EMT on MCs and combines with physiologic dialysate simultaneously may ameliorate it.
1. Huang CC, Cheng KF, Wu HD. Survival analysis: comparing peritoneal dialysis and hemodialysis in Taiwan. Perit Dial Int 2008; 28 Suppl 3: S15-20.
2. Vonesh EF, Snyder JJ, Foley RN, et al. Mortality studies comparing peritoneal dialysis and hemodialysis: what do they tell us? Kidney Int Suppl 2006: S3-11.
3. Fenton SS, Schaubel DE, Desmeules M, et al. Hemodialysis versus peritoneal dialysis: a comparison of adjusted mortality rates. Am J Kidney Dis 1997; 30: 334-342.
4. Mehrotra R, Chiu YW, Kalantar-Zadeh K, et al. Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease. Arch Intern Med 2011; 171: 110-118.
5. Tokgoz B. Clinical advantages of peritoneal dialysis. Perit Dial Int 2009; 29 Suppl 2: S59-61.
6. Kawaguchi Y, Hasegawa T, Nakayama M, et al. Issues affecting the longevity of the continuous peritoneal dialysis therapy. Kidney Int Suppl 1997; 62: S105-107.
7. Schaefer F, Klaus G, Muller-Wiefel DE, et al. Current practice of peritoneal dialysis in children: results of a longitudinal survey. Mid European Pediatric Peritoneal Dialysis Study Group (MEPPS). Perit Dial Int 1999; 19 Suppl 2: S445-449.
8. Han SH, Lee SC, Ahn SV, et al. Improving outcome of CAPD: twenty-five years' experience in a single Korean center. Perit Dial Int 2007; 27: 432-440.
9. Woodrow G, Turney JH, Brownjohn AM. Technique failure in peritoneal dialysis and its impact on patient survival. Perit Dial Int 1997; 17: 360-364.
10. Nakamoto H, Kawaguchi Y, Suzuki H. Is technique survival on peritoneal dialysis better in Japan? Perit Dial Int 2006; 26: 136-143.
11. Andreoli SP, Langefeld CD, Stadler S, et al. Risks of peritoneal membrane failure in children undergoing long-term peritoneal dialysis. Pediatr Nephrol 1993; 7: 543-547.
12. Davies SJ, Phillips L, Griffiths AM, et al. What really happens to people on long-term peritoneal dialysis? Kidney Int 1998; 54: 2207-2217.
13. Krediet RT. The peritoneal membrane in chronic peritoneal dialysis. Kidney Int 1999; 55: 341-356.
14. Davies SJ, Phillips L, Naish PF, et al. Peritoneal glucose exposure and changes in membrane solute transport with time on peritoneal dialysis. J Am Soc Nephrol 2001; 12: 1046-1051.
15. Holmes CJ, Faict D. Peritoneal dialysis solution biocompatibility: definitions and evaluation strategies. Kidney Int Suppl 2003: S50-56.
16. Williams JD, Craig KJ, Topley N, et al. Morphologic changes in the peritoneal membrane of patients with renal disease. J Am Soc Nephrol 2002; 13: 470-479.
17. Mateijsen MA, van der Wal AC, Hendriks PM, et al. Vascular and interstitial changes in the peritoneum of CAPD patients with peritoneal sclerosis. Perit Dial Int 1999; 19: 517-525.
18. Plum J, Hermann S, Fussholler A, et al. Peritoneal sclerosis in peritoneal dialysis patients related to dialysis settings and peritoneal transport properties. Kidney Int Suppl 2001; 78: S42-47.
19. Margetts PJ, Bonniaud P. Basic mechanisms and clinical implications of peritoneal fibrosis. Perit Dial Int 2003; 23: 530-541.
20. Di Paolo N, Sacchi G. Atlas of peritoneal histology. Perit Dial Int 2000; 20 Suppl 3: S5-96.
21. Nagy JA. Peritoneal membrane morphology and function. Kidney Int Suppl 1996; 56: S2-11.
22. Fischbach M, Haraldsson B, Helms P, et al. The peritoneal membrane: a dynamic dialysis membrane in children. Adv Perit Dial 2003; 19: 265-268.
23. Dobbie JW. New concepts in molecular biology and ultrastructural pathology of the peritoneum: their significance for peritoneal dialysis. Am J Kidney Dis 1990; 15: 97-109.
24. Lopez-Cabrera M, Aguilera A, Aroeira LS, et al. Ex vivo analysis of dialysis effluent-derived mesothelial cells as an approach to unveiling the mechanism of peritoneal membrane failure. Perit Dial Int 2006; 26: 26-34.
25. Williams JD, Craig KJ, von Ruhland C, et al. The natural course of peritoneal membrane biology during peritoneal dialysis. Kidney Int Suppl 2003: S43-49.
26. Vargha R, Endemann M, Kratochwill K, et al. Ex vivo reversal of in vivo transdifferentiation in mesothelial cells grown from peritoneal dialysate effluents. Nephrol Dial Transplant 2006; 21: 2943-2947.
27. Yanez-Mo M, Lara-Pezzi E, Selgas R, et al. Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 2003; 348: 403-413.
28. Sherif AM, Nakayama M, Maruyama Y, et al. Quantitative assessment of the peritoneal vessel density and vasculopathy in CAPD patients. Nephrol Dial Transplant 2006; 21: 1675-1681.
29. Margetts PJ, Gyorffy S, Kolb M, et al. Antiangiogenic and antifibrotic gene therapy in a chronic infusion model of peritoneal dialysis in rats. J Am Soc Nephrol 2002; 13: 721-728.
30. Krediet RT, Lindholm B, Rippe B. Pathophysiology of peritoneal membrane failure. Perit Dial Int 2000; 20 Suppl 4: S22-42.
31. Lai KN, Tang SC, Leung JC. Mediators of inflammation and fibrosis. Perit Dial Int 2007; 27 Suppl 2: S65-71.
32. Aroeira LS, Aguilera A, Selgas R, et al. Mesenchymal conversion of mesothelial cells as a mechanism responsible for high solute transport rate in peritoneal dialysis: role of vascular endothelial growth factor. Am J Kidney Dis 2005; 46: 938-948.
33. Jimenez-Heffernan JA, Aguilera A, Aroeira LS, et al. Immunohistochemical characterization of fibroblast subpopulations in normal peritoneal tissue and in peritoneal dialysis-induced fibrosis. Virchows Arch 2004; 444: 247-256.
34. Kim KK, Kugler MC, Wolters PJ, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 2006; 103: 13180-13185.
35. Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 2007; 282: 23337-23347.
36. Iwano M, Plieth D, Danoff TM, et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002; 110: 341-350.
37. Strutz F, Okada H, Lo CW, et al. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 1995; 130: 393-405.
38. Okada H, Danoff TM, Kalluri R, et al. Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 1997; 273: F563-574.
39. Rastaldi MP, Ferrario F, Giardino L, et al. Epithelial-mesenchymal transition of tubular epithelial cells in human renal biopsies. Kidney Int 2002; 62: 137-146.
40. Zeisberg M, Hanai J, Sugimoto H, et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 2003; 9: 964-968.
41. Margetts PJ, Bonniaud P, Liu L, et al. Transient overexpression of TGF-{beta}1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol 2005; 16: 425-436.
42. Powell DW, Mifflin RC, Valentich JD, et al. Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 1999; 277: C1-9.
43. Bucala R, Spiegel LA, Chesney J, et al. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med 1994; 1: 71-81.
44. Zeisberg EM, Tarnavski O, Zeisberg M, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 2007; 13: 952-961.
45. Potenta S, Zeisberg E, Kalluri R. The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer 2008; 99: 1375-1379.
46. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119: 1420-1428.
47. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003; 112: 1776-1784.
48. Aroeira LS, Lara-Pezzi E, Loureiro J, et al. Cyclooxygenase-2 mediates dialysate-induced alterations of the peritoneal membrane. J Am Soc Nephrol 2009; 20: 582-592.
49. Del Peso G, Jimenez-Heffernan JA, Bajo MA, et al. Epithelial-to-mesenchymal transition of mesothelial cells is an early event during peritoneal dialysis and is associated with high peritoneal transport. Kidney Int Suppl 2008: S26-33.
50. Pecoits-Filho R, Araujo MR, Lindholm B, et al. Plasma and dialysate IL-6 and VEGF concentrations are associated with high peritoneal solute transport rate. Nephrol Dial Transplant 2002; 17: 1480-1486.
51. Zweers MM, de Waart DR, Smit W, et al. Growth factors VEGF and TGF-beta1 in peritoneal dialysis. J Lab Clin Med 1999; 134: 124-132.
52. Mandl-Weber S, Cohen CD, Haslinger B, et al. Vascular endothelial growth factor production and regulation in human peritoneal mesothelial cells. Kidney Int 2002; 61: 570-578.
53. Aroeira LS, Aguilera A, Sanchez-Tomero JA, et al. Epithelial to mesenchymal transition and peritoneal membrane failure in peritoneal dialysis patients: pathologic significance and potential therapeutic interventions. J Am Soc Nephrol 2007; 18: 2004-2013.
54. Lai KN, Leung JC. Inflammation in peritoneal dialysis. Nephron Clin Pract 2010; 116: c11-18.
55. Do JY, Kim YL, Park JW, et al. The association between the vascular endothelial growth factor-to-cancer antigen 125 ratio in peritoneal dialysis effluent and the epithelial-to-mesenchymal transition in continuous ambulatory peritoneal dialysis. Perit Dial Int 2008; 28 Suppl 3: S101-106.
56. Bajo MA, Perez-Lozano ML, Albar-Vizcaino P, et al. Low-GDP peritoneal dialysis fluid ('balance') has less impact in vitro and ex vivo on epithelial-to-mesenchymal transition (EMT) of mesothelial cells than a standard fluid. Nephrol Dial Transplant 2011; 26: 282-291.
57. Do JY, Kim YL, Park JW, et al. The effect of low glucose degradation product dialysis solution on epithelial-to-mesenchymal transition in continuous ambulatory peritoneal dialysis patients. Perit Dial Int 2005; 25 Suppl 3: S22-25.
58. Araki-Sasaki K, Ohashi Y, Sasabe T, et al. An SV40-immortalized human corneal epithelial cell line and its characterization. Invest Ophthalmol Vis Sci 1995; 36: 614-621.
59. Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994; 331: 1286-1292.
60. Erixon M, Wieslander A, Linden T, et al. How to avoid glucose degradation products in peritoneal dialysis fluids. Perit Dial Int 2006; 26: 490-497.
61. Ha H, Yu MR, Choi HN, et al. Effects of conventional and new peritoneal dialysis solutions on human peritoneal mesothelial cell viability and proliferation. Perit Dial Int 2000; 20 Suppl 5: S10-18.
62. Julian Lewis MR, Keith Roberts, Alexander Johnson, Peter Walter, Bruce Alberts. Molecular Biology of the Cell, Fifth Edition 2008.
校內：2016-08-30公開校外：2016-08-30公開