進階搜尋


 
系統識別號 U0026-0812200910442776
論文名稱(中文) 腸病毒71型感染內皮細胞株HMEC-1對其生物特性之影響
論文名稱(英文) Effects of enterovirus 71 infection on the biological functions of endothelial cells
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 91
學期 2
出版年 92
研究生(中文) 梁純淨
研究生(英文) Chun-Ching Liang
學號 s4690407
學位類別 碩士
語文別 中文
論文頁數 85頁
口試委員 召集委員-王貞仁
口試委員-陳舜華
口試委員-林貴香
指導教授-葉才明
中文關鍵字 內皮細胞  腸病毒71型  通透性  細胞激素 
英文關鍵字 endothelial cells  enterovirus 71  permeability  cytokine 
學科別分類
中文摘要 台灣於1998年發生大規模的腸病毒71型流行,隨後幾年仍陸續有病案產生。腸病毒71型屬於小RNA病毒科(Picornaviridae)為單正股之RNA病毒,其病症不一從輕微的手足口症、咽唊炎到無菌性腦膜炎、腦炎、肺水腫甚至死亡。目前對腸病毒71型如何從入侵處的腸道、呼吸道及鄰近的淋巴組織增殖之後藉病毒血症移行感染至較遠的器官組織例如中樞神經的過程仍有些不清楚。腸病毒如何穿越血管內皮的可能原因為直接感染內皮細胞、藉胞飲作用穿過血管層或因感染使細胞層的通透性增大令攜帶病毒的血球順利穿越侵犯至他處。本實驗使用人類微血管內皮細胞株(HMEC-1)來探討腸病毒71型對其感染的可能性。利用免疫螢光抗體染色可偵測到感染細胞的細胞質中有腸病毒71型抗原,以溶斑分析法可以定量出病毒感染的效率,而病毒感染後也可以觀察到細胞病變及細胞凋亡的現象。更進一步探討病毒感染後對HMEC-1的影響中發現只有活的腸病毒71型才可以順利感染並可刺激HMEC-1細胞表面吸附因子ICAM-1和VCAM-1表現增多且其TLR-4分子亦增多。活病毒感染內皮細胞同時可使之產生發炎性的細胞激素譬如IL-6及吞噬細胞移動抑制分子MIF及趨化素MCP-1,而且可以增強白血球對內皮細胞的吸附能力,也可以使細胞層通透性增大。此外使用乳鐵蛋白lactoferrin或免疫球蛋白IVIG來干擾腸病毒71型對內皮細胞的感染時發現加入足量內含中和效價的IVIG可以阻止病毒的感染,而乳鐵蛋白有抑制病毒感染的效果。由種種跡象可以推測腸病毒71型感染內皮細胞時可引起發炎反應吸引免疫細胞至感染區並引起強烈的免疫反應,病毒可能依此方式散播至重要的病灶區例如中樞神經或肺部等並引起嚴重的臨床症狀。此外乳鐵蛋白及IVIG則可有效抑制腸病毒71型感染內皮細胞,因此在腸病毒71型感染的預防或治療上或許可以加以應用。
英文摘要 Enterovirus 71 (EV71) is a positive-stranded RNA virus belonging to the family of Picornaviridae, which caused a large outbreak in Taiwan in 1998. The clinical manifestations caused by EV71 infection vary from mild hand-foot-and mouth disease or herpangina to aseptic meningitis, encephalitis, pulmonary edema and death. However, it is unclear how EV71 is transmitted from initial replication sites to distal target tissues such as central nerve system (CNS). It is possible EV71 may pass through vascular endothelium by infection or by transcytosis or be carried past the barrier by infected circulating cells to invade other tissues. In this study, the possibility of EV71 infection of human endothelial cells was studied using human microvascular endothelial cell line (HMEC-1 cell). EV71 antigens were detected in the cytoplasm of EV71-infected cells by immunofluorescent stain. EV71 infection of endothelial cells was further confirmed by the increase of virus plaque forming unit in the supernatants and cell lysates of EV71 infected HMEC-1 cells. In addition, only live but not UV-inactivated EV71 induced the cytopathic change and apoptosis of HMEC-1 cells. Furthermore, the expression of several surface molecules such as ICAM-1, VCAM-1 and toll-like receptor 4 (TLR4) were increased in EV71-infected cells. The productions of pro-inflammatory cytokines such as IL-6 and macrophage migration inhibition factor (MIF) and chemokine such as macrophage chemo- attractant protein 1(MCP-1) were also induced by EV71 infection of HMEC-1 cells. EV 71 also enhanced the ability of leukocyte adhesion and increased the permeability of HMEC-1 monolayer cells. Intravenous immune globulin (IVIG) was able to block EV 71 infection of HMEC-1 cells. However, lactoferrin also showed the inhibitory effects against EV71 infection. In summary, infection of endothelial cells by EV71 may trigger inflammation and attract immune cells to local infected tissue, which may play important roles in transmission of EV71 from peripheral tissue to blood and to CNS or other target tissues. In addition, lactoferrin and IVIG can inhibit EV71 infection of HMEC-1 cells effectively, which may be useful to prevent or treat EV71 infected patients.
論文目次 總 目 錄
總目錄………………………………………………………………... I
縮寫指引……………………………………………………………... IV
圖目錄………………………………………………………………... VI
緒論…………………………………………………………………... 1
研究動機與實驗架構………………………………………………... 17
材料及方法…………………………………………………………... 19
A. 材料……………………………………………………………….. 19
A-1 儀器……………………………………………………………... 19
A-2 試劑……………………………………………………………... 20
B 方法……………………………………………………………… 23
第一節 腸病毒71型感染細胞模式之建立………………………… 23
1. 細胞培養………………………………………………………… 23
2. 病毒的培養……………………………………………………… 24
3. EV71病毒感染細胞之確定……………………………………... 26
4. EV71病毒感染細胞之生長分析………………………………... 27
5. 病毒感染後細胞病變……………………………………………. 27
第二節 腸病毒71型感染影響內皮細胞株功能…………………… 30
1. 利用細胞流速儀觀察感染後細胞表層VCAM-1的變化……… 30
2. 免疫螢光染色法觀察感染後細胞表面抗原的變化……………. 31
3. 酵素免疫法監測細胞感染後產生細胞激素及趨化素………… 32
4. 細胞受病毒感染後與白血球吸附情形…………………………. 34
5. 病毒感染影響單層內皮細胞通透性情形………………………. 35
第三節 藥物或抗體影響內皮細胞株感染腸病毒71型…………… 36
1. 乳鐵蛋白lactoferrin和腸病毒71型的作用…………………… 36
2. 免疫球蛋白IVIG和腸病毒71型的作用………………………. 36
第四節 統計方法……………………………………………………. 37
結果…………………………………………………………………... 38
第一節 腸病毒71型感染HMEC-1內皮細胞之確認…………….. 38
1. 腸病毒71型感染引起細胞病變………………………………… 38
2. 腸病毒71型感染之生長速率分析……………………………… 38
3. 腸病毒71型比克沙奇病毒A16型感染細胞有較好的生長速率 39
4. 腸病毒71型感染造成HMEC-1細胞存活率下降…………….. 40
第二節 腸病毒71型感染影響HMEC-1內皮細胞株功能………… 41
1. 病毒感染增加細胞表面VCAM-1、ICAM-1及TLR4表現……. 41
2. 病毒感染誘發細胞分泌IL6,MIF及MCP-1………………. 42
3. 病毒刺激增加白血球與HMEC-1細胞間的黏著能力………… 43
4. 病毒感染影響HMEC-1單層細胞的通透性………………….. 44
第三節 藥物或抗體影響HMEC-1內皮細胞株感染腸病毒71型... 45
1. 乳鐵蛋白lactoferrin可抑制病毒生長………………………… 45
2. 免疫球蛋白IVIG抑制病毒生長……………………………… 45
討論………………………………………………………………….. 47
參考文獻…………………………………………………………….. 57
圖附錄……………………………………………………………….. 69
自述………………………………………………………………….. 85
參考文獻 1. Melnick, J. L. (1996). Enteroviruses: poliovirus, coxsackieviruses, echoviruses, and newer enteroviruses. P. 655-712. In B. N. Fields, D. M. Knipe, P. M. Howley, R. M. Chanock, J. L. Melnick, Y. P. Monath, B. Roizman, and S. E. Straus (ed.), Virology, 3rd ed. Lippincott-Raven, Philadelphia, Pa.

2. Danes, L., E. Sladka, J. Hancil, and J. Horacek. 1988. Cross reactivity among human enterovirus serotypes as revealed by microneutralization assay technique. J Hyg Epidemiol Microbiol Immunol 32:233.

3. Brown, B. A., and M. A. Pallansch. 1995. Complete nucleotide sequence of enterovirus 71 is distinct from poliovirus. Virus Res 39:195.

4. Pestova, T. V., C. U. Hellen, and E. Wimmer. 1994. A conserved AUG triplet in the 5' nontranslated region of poliovirus can function as an initiation codon in vitro and in vivo. Virology 204:729.

5. Schmid, M., and E. Wimmer. 1994. IRES-controlled protein synthesis and genome replication of poliovirus. Arch Virol Suppl 9:279.

6. Nicholson, R., J. Pelletier, S. Y. Le, and N. Sonenberg. 1991. Structural and functional analysis of the ribosome landing pad of poliovirus type 2: in vivo translation studies. J Virol 65:5886.

7. Toyoda, H., M. J. Nicklin, M. G. Murray, C. W. Anderson, J. J. Dunn, F. W. Studier, and E. Wimmer. 1986. A second virus-encoded proteinase involved in proteolytic processing of poliovirus polyprotein. Cell 45:761.

8. Nicklin, M. J., H. G. Krausslich, H. Toyoda, J. J. Dunn, and E. Wimmer. 1987. Poliovirus polypeptide precursors: expression in vitro and processing by exogenous 3C and 2A proteinases. Proc Natl Acad Sci U S A 84:4002.

9. Garcia, M. I., M. Perez, M. Caruso, O. Sthandier, R. Ferreira, M. Cermola, C. Macchia, and P. Amati. 2000. A mutation in the DE loop of the VP1 protein that prevents polyomavirus transcription and replication. Virology 272:293

10. Baxt, B., D. O. Morgan, B. H. Robertson, and C. A. Timpone. 1984. Epitopes on foot-and-mouth disease virus outer capsid protein VP1 involved in neutralization and cell attachment. J Virol 51:298.

11. Wetz, K., and K. O. Habermehl. 1982. Specific cross-linking of capsid proteins to virus RNA by ultraviolet irradiation of poliovirus. J Gen Virol 59:397.

12. Bernstein, H. D., N. Sonenberg, and D. Baltimore. 1985. Poliovirus mutant that does not selectively inhibit host cell protein synthesis. Mol Cell Biol 5:2913.

13. Li, J. P., and D. Baltimore. 1988. Isolation of poliovirus 2C mutants defective in viral RNA synthesis. J Virol 62:4016.

14. Gorbalenya, A. E., V. M. Blinov, and A. P. Donchenko. 1986. Poliovirus-encoded proteinase 3C: a possible evolutionary link between cellular serine and cysteine proteinase families. FEBS Lett 194:253.

15. Jore, J., B. De Geus, R. J. Jackson, P. H. Pouwels, and B. E. Enger-Valk. 1988. Poliovirus protein 3CD is the active protease for processing of the precursor protein P1 in vitro. J Gen Virol 69 ( Pt 7):1627.

16. Lama, J., A. V. Paul, K. S. Harris, and E. Wimmer. 1994. Properties of purified recombinant poliovirus protein 3aB as substrate for viral proteinases and as co-factor for RNA polymerase 3Dpol. J Biol Chem 269:66.

17. Deitz, S. B., D. A. Dodd, S. Cooper, P. Parham, and K. Kirkegaard. 2000. MHC I-dependent antigen presentation is inhibited by poliovirus protein 3A. Proc Natl Acad Sci U S A 97:13790.

18. Dodd, D. A., T. H. Giddings, Jr., and K. Kirkegaard. 2001. Poliovirus 3A protein limits interleukin-6 (IL-6), IL-8, and beta interferon secretion during viral infection. J Virol 75:8158.

19. Mendelsohn, C. L., E. Wimmer, and V. R. Racaniello. 1989. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 56:855.

20. Reagan, K. J., B. Goldberg, and R. L. Crowell. 1984. Altered receptor specificity of coxsackievirus B3 after growth in rhabdomyosarcoma cells. J Virol 49:635.

21. Harper, D.R. (1998). Molecular Virology. 2nd edition

22. Fricks, C. E., and J. M. Hogle. 1990. Cell-induced conformational change in poliovirus: externalization of the amino terminus of VP1 is responsible for liposome binding. J Virol 64:1934.

23. Schmidt, N. J., E. H. Lennette, and H. H. Ho. 1974. An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 129:304.

24. Alexander, J. P., Jr., L. Baden, M. A. Pallansch, and L. J. Anderson. 1994. Enterovirus 71 infections and neurologic disease--United States, 1977-1991. J Infect Dis 169:905.

25. Chumakov, M., M. Voroshilova, L. Shindarov, I. Lavrova, L. Gracheva, G. Koroleva, S. Vasilenko, I. Brodvarova, M. Nikolova, S. Gyurova, M. Gacheva, G. Mitov, N. Ninov, E. Tsylka, I. Robinson, M. Frolova, V. Bashkirtsev, L. Martiyanova, and V. Rodin. 1979. Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol 60:329.

26. Chumakov, K. M., I. K. Lavrova, L. I. Martianova, M. B. Korolev, V. N. Bashkirtsev, and M. K. Voroshilova. 1979. Investigation of physicochemical properties of Bulgarian strain 258 of enterovirus type 71. Brief report. Arch Virol 60:359.

27. Tagaya, I., and Y. Moritsugu. 1973. Epidemic of hand, foot and mouth disease in Japan. Jpn J Med Sci Biol 26:143.

28. Hagiwara, A., I. Tagaya, and T. Komatsu. 1979. Seroepidemiology of enterovirus 71 among healthy children near Tokyo. Microbiol Immunol 23:121.

29. Anonymous. National Institute of Infectious Diseases. 1998. Hand-foot-and- mouth disease. Infectous Agents Surveillance Report. 19: 150-151

30. Nagy, G., S. Takatsy, E. Kukan, I. Mihaly, and I. Domok. 1982. Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol 71:217.

31. Freymuth, F., C. Duncombe, A. Hardouin, B. Boutard, J. Guihard, and D. Leroy. 1981. [Isolation of enterovirus 71 in hand-foot-and mouth disease]. Nouv Presse Med 10:2210.

32. AbuBakar, S., H. Y. Chee, M. F. Al-Kobaisi, J. Xiaoshan, K. B. Chua, and S. K. Lam. 1999. Identification of enterovirus 71 isolates from an outbreak of hand, foot and mouth disease (HFMD) with fatal cases of encephalomyelitis in Malaysia. Virus Res 61:1.

33. McMinn, P., I. Stratov, and G. Dowse. 1999. Enterovirus 71 outbreak in Western Australia associated with acute flaccid paralysis. Preliminary report. Commun Dis Intell 23:199.

34. Wu, T. N., S. F. Tsai, S. F. Li, T. F. Lee, T. M. Huang, M. L. Wang, K. H. Hsu, and C. Y. Shen. 1999. Sentinel surveillance for enterovirus 71, Taiwan, 1998. Emerg Infect Dis 5:458.

35. Ho, M., E. R. Chen, K. H. Hsu, S. J. Twu, K. T. Chen, S. F. Tsai, J. R. Wang, and S. R. Shih. 1999. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 341:929.

36. Wang, J. R., Y. C. Tuan, H. P. Tsai, J. J. Yan, C. C. Liu, and I. J. Su. 2002. Change of major genotype of enterovirus 71 in outbreaks of hand-foot-and-mouth disease in Taiwan between 1998 and 2000. J Clin Microbiol 40:10.

37 Chu, P. Y., K. H. Lin, K. P. Hwang, L. C. Chou, C. F. Wang, S. R. Shih, J. R. Wang, Y. Shimada, H.Ishiko. 2001. Molecular epidemiology of enterovirus 71 in Taiwan. Arch Virol 146: 589

38. Huang, C. C., C. C. Liu, Y. C. Chang, C. Y. Chen, S. T. Wang, and T. F. Yeh. 1999. Neurologic complications in children with enterovirus 71 infection. N Engl J Med 341:936.

39. Chang, L. Y., Y. C. Huang, and T. Y. Lin. 1998. Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease. Lancet 352:367.

40. Chang, L. Y., T. Y. Lin, K. H. Hsu, Y. C. Huang, K. L. Lin, C. Hsueh, S. R. Shih, H. C. Ning, M. S. Hwang, H. S. Wang, and C. Y. Lee. 1999. Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet 354:1682.

41. Baker, A. B. (1957). Poliomyelitis 16: a study of pulmonary edema. Neurology 7, 743-751.

42. Ali, M. H., S. A. Schlidt, N. S. Chandel, K. L. Hynes, P. T. Schumacker, and B. L. Gewertz. 1999. Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction. Am J Physiol 277:L1057.

43. Yu, A. C., and L. T. Lau. 2000. Expression of interleukin-1 alpha, tumor necrosis factor alpha and interleukin-6 genes in astrocytes under ischemic injury. Neurochem Int 36:369.

44. Tsao, K. C., E. C. Chan, L. Y. Chang, P. Y. Chang, C. G. Huang, Y. P. Chen, S. C. Chang, T. Y. Lin, C. F. Sun, and S. R. Shih. 2002. Responses of IgM for enterovirus 71 infection. J Med Virol 68:574.

45 Tsao,K.C., (2003) EV71 IgM, IgA and IgG development. Enterovirus 71 in Taiwan : past and future symposium in Taoyuan.

46. Ishimaru, Y., S. Nakano, K. Yamaoka, and S. Takami. 1980. Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system. Arch Dis Child 55:583.

47. Liu, C. C., H. W. Tseng, S. M. Wang, J. R. Wang, and I. J. Su. 2000. An outbreak of enterovirus 71 infection in Taiwan, 1998: epidemiologic and clinical manifestations. J Clin Virol 17:23.

48. Hagiwara, A., T. Yoneyama, and I. Hashimoto. 1983. Isolation of a temperature-sensitive strain of enterovirus 71 with reduced neurovirulence for monkeys. J Gen Virol 64 (Pt 2):499.

49. 郭品樺(2001)腸病毒71型感染生物特性之研究Studies of biological properties of h enterovirus 71 infection國立成功大學分子醫學研究所碩士論文。

50. Shih, S. R., M. S. Ho, K. H. Lin, S. L. Wu, Y. T. Chen, C. N. Wu, T. Y. Lin, L. Y. Chang, K. C. Tsao, H. C. Ning, P. Y. Chang, S. M. Jung, C. Hsueh, and K. S. Chang. 2000. Genetic analysis of enterovirus 71 isolated from fatal and non-fatal cases of hand, foot and mouth disease during an epidemic in Taiwan, 1998. Virus Res 68:127.

51. Chonmaitree, T., C. Ford, C. Sanders, and H. L. Lucia. 1988. Comparison of cell cultures for rapid isolation of enteroviruses. J Clin Microbiol 26:2576.

52. Wen, Y. Y., T. Y. Chang, S. T. Chen, C. Li, and H. S. Liu. 2003. Comparative study of enterovirus 71 infection of human cell lines. J Med Virol 70:109.

53. Li, M. L., T. A. Hsu, T. C. Chen, S. C. Chang, J. C. Lee, C. C. Chen, V. Stollar, and S. R. Shih. 2002. The 3C protease activity of enterovirus 71 induces human neural cell apoptosis. Virology 293:386.

54. Kuo, R. L., S. H. Kung, Y. Y. Hsu, and W. T. Liu. 2002. Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. J Gen Virol 83:1367.

55. 孔建民Chien-Min Kung(1999)台灣地區分離之腸病毒71型之趨細胞性及其基因變異之分析Cellular Tropism and Genetic Variation of Enterovirus Type 71 Isolated in Taiwan. 國立臺灣大醫事技術學研究所碩士論文

56. Whyllie, A. H. (1997). Apoptosis: an overview. British medical Bulletin 53, 451-465.

57. Marttila, J., H. Hyoty, P. Vilja, T. Harkonen, A. Alho, M. Roivainen, T. Hyypia, and J. Ilonen. 2002. T cell epitopes in coxsackievirus B4 structural proteins concentrate in regions conserved between enteroviruses. Virology 293:217
.
58. Lin, T. Y., L. Y. Chang, Y. C. Huang, K. H. Hsu, C. H. Chiu, and K. D. Yang. 2002. Different proinflammatory reactions in fatal and non-fatal enterovirus 71 infections: implications for early recognition and therapy. Acta Paediatr 91:632.

59. Baugh, J. A., and R. Bucala. 2002. Macrophage migration inhibitory factor. Crit Care Med 30:S27.

60. Lue, H., R. Kleemann, T. Calandra, T. Roger, and J. Bernhagen. 2002. Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect 4:449.

61. Calandra, T., B. Echtenacher, D. L. Roy, J. Pugin, C. N. Metz, L. Hultner, D. Heumann, D. Mannel, R. Bucala, and M. P. Glauser. 2000. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6:164.

62. Roger, T., J. David, M. P. Glauser, and T. Calandra. 2001. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature 414:920.

63. Arndt, U., G. Wennemuth, P. Barth, M. Nain, Y. Al-Abed, A. Meinhardt, D. Gemsa, and M. Bacher. 2002. Release of macrophage migration inhibitory factor and CXCL8/interleukin-8 from lung epithelial cells rendered necrotic by influenza A virus infection. J Virol 76:9298.

64. Bacher, M., M. Eickmann, J. Schrader, D. Gemsa, and A. Heiske. 2002. Human cytomegalovirus-mediated induction of MIF in fibroblasts. Virology 299:32.

65. Kaiser, L., and H. V. Sparks, Jr. 1987. Endothelial cells. Not just a cellophane wrapper. Arch Intern Med 147:569.

66. Carson, S. D., J. T. Hobbs, S. M. Tracy, and N. M. Chapman. 1999. Expression of the coxsackievirus and adenovirus receptor in cultured human umbilical vein endothelial cells: regulation in response to cell density. J Virol 73:7077.

67. Avirutnan, P., P. Malasit, B. Seliger, S. Bhakdi, and M. Husmann. 1998. Dengue virus infection of human endothelial cells leads to chemokine production, complement activation, and apoptosis. J Immunol 161:6338.

68. Friedman, H. M., E. J. Macarak, R. R. MacGregor, J. Wolfe, and N. A. Kefalides. 1981. Virus infection of endothelial cells. J Infect Dis 143:266.

69. Conaldi, P. G., C. Serra, A. Mossa, V. Falcone, F. Basolo, G. Camussi, A. Dolei, and A. Toniolo. 1997. Persistent infection of human vascular endothelial cells by group B coxsackieviruses. J Infect Dis 175:693.

70. Saijets, S., P. Ylipaasto, O. Vaarala, T. Hovi, and M. Roivainen. 2003. Enterovirus infection and activation of human umbilical vein endothelial cells. J Med Virol 70:430.

71. MacGregor, R. R., H. M. Friedman, E. J. Macarak, and N. A. Kefalides. 1980. Virus infection of endothelial cells increases granulocyte adherence. J Clin Invest 65:1469.

72. Vuorinen, T., R. Vainionpaa, J. Heino, and T. Hyypia. 1999. Enterovirus receptors and virus replication in human leukocytes. J Gen Virol 80 ( Pt 4):921.

73. Zurbriggen, A., and R. S. Fujinami. 1988. Theiler's virus infection in nude mice: viral RNA in vascular endothelial cells. J Virol 62:3589.

74. Zietz, C., B. Hotz, M. Sturzl, E. Rauch, R. Penning, and U. Lohrs. 1996. Aortic endothelium in HIV-1 infection: chronic injury, activation, and increased leukocyte adherence. Am J Pathol 149:1887.

75. Grundy, J. E., K. M. Lawson, L. P. MacCormac, J. M. Fletcher, and K. L. Yong. 1998. Cytomegalovirus-infected endothelial cells recruit neutrophils by the secretion of C-X-C chemokines and transmit virus by direct neutrophil-endothelial cell contact and during neutrophil transendothelial migration. J Infect Dis 177:1465.

76. Harcourt, B. H., P. A. Rota, K. B. Hummel, W. J. Bellini, and M. K. Offermann. 1999. Induction of intercellular adhesion molecule 1 gene expression by measles virus in human umbilical vein endothelial cells. J Med Virol 57:9.

77. Huang, Y. H., H. Y. Lei, H. S. Liu, Y. S. Lin, C. C. Liu, and T. M. Yeh. 2000. Dengue virus infects human endothelial cells and induces IL-6 and IL-8 production. Am J Trop Med Hyg 63:71.

78. Cho, N. H., S. Y. Seong, M. S. Huh, N. H. Kim, M. S. Choi, and I. S. Kim. 2002. Induction of the gene encoding macrophage chemoattractant protein 1 by Orientia tsutsugamushi in human endothelial cells involves activation of transcription factor activator protein 1. Infect Immun 70:4841.

79. Takashima, H., K. Eguchi, A. Kawakami, Y. Kawabe, K. Migita, M. Sakai, T. Origuchi, and S. Nagataki. 1996. Cytokine production by endothelial cells infected with human T cell lymphotropic virus type I. Ann Rheum Dis 55:632.

80. Duchini, A., S. Govindarajan, M. Santucci, G. Zampi, and F. M. Hofman. 1996. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 44:474.

81. Pober, J. S., and R. S. Cotran. 1990. Cytokines and endothelial cell biology. Physiol Rev 70:427.

82. Kurt-Jones, E. A., L. Popova, L. Kwinn, L. M. Haynes, L. P. Jones, R. A. Tripp, E. E. Walsh, M. W. Freeman, D. T. Golenbock, L. J. Anderson, and R. W. Finberg. 2000. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1:398.

83. Faure, E., O. Equils, P. A. Sieling, L. Thomas, F. X. Zhang, C. J. Kirschning, N. Polentarutti, M. Muzio, and M. Arditi. 2000. Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem 275:11058.

84. Ades, E. W., F. J. Candal, R. A. Swerlick, V. G. George, S. Summers, D. C. Bosse, and T. J. Lawley. 1992. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. J Invest Dermatol 99:683.

85. Goebeler, M., T. Yoshimura, A. Toksoy, U. Ritter, E. B. Brocker, and R. Gillitzer. 1997. The chemokine repertoire of human dermal microvascular endothelial cells and its regulation by inflammatory cytokines. J Invest Dermatol 108:445.

86. van der Strate, B. W., L. Beljaars, G. Molema, M. C. Harmsen, and D. K. Meijer. 2001. Antiviral activities of lactoferrin. Antiviral Res 52:225.

87. Lin, T. Y., C. Chu, and C. H. Chiu. 2002. Lactoferrin inhibits enterovirus 71 infection of human embryonal rhabdomyosarcoma cells in vitro. J Infect Dis 186:1161.

88. Samuelsson, A., T. L. Towers, and J. V. Ravetch. 2001. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 291:484.

89. Hagiwara, A., I. Tagaya, and T. Yoneyama. 1978. Common antigen between coxsackievirus A 16 and enterovirus 71. Microbiol Immunol 22:81.

90. Chow, K. C., C. C. Lee, T. Y. Lin, W. C. Shen, J. H. Wang, and C. T. Peng. 2000. Congenital enterovirus 71 infection: a case study with virology and immunohistochemistry. Clin Infect Dis 31:509.

91. Dhawan, S., R. K. Puri, A. Kumar, H. Duplan, J. M. Masson, and B. B. Aggarwal. 1997. Human immunodeficiency virus-1-tat protein induces the cell surface expression of endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in human endothelial cells. Blood 90:1535.

92. Craigen, J. L., K. L. Yong, N. J. Jordan, L. P. MacCormac, J. Westwick, A. N. Akbar, and J. E. Grundy. 1997. Human cytomegalovirus infection up-regulates interleukin-8 gene expression and stimulates neutrophil transendothelial migration. Immunology 92:138.

93. Guetta, E., V. Guetta, T. Shibutani, and S. E. Epstein. 1997. Monocytes harboring cytomegalovirus: interactions with endothelial cells, smooth muscle cells, and oxidized low-density lipoprotein. Possible mechanisms for activating virus delivered by monocytes to sites of vascular injury. Circ Res 81:8.

94. Irani, D. N., and D. E. Griffin. 1996. Regulation of lymphocyte homing into the brain during viral encephalitis at various stages of infection. J Immunol 156:3850.

95. Lin, T. Y., S. H. Hsia, Y. C. Huang, C. T. Wu, and L. Y. Chang. 2003. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis 36:269.

96. Pinsky, M. R., J. L. Vincent, J. Deviere, M. Alegre, R. J. Kahn, and E. Dupont. 1993. Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest 103:565.

97. Ichiyama, T., M. Nishikawa, T. Yoshitomi, T. Hayashi, and S. Furukawa. 1998. Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 in cerebrospinal fluid from children with prolonged febrile seizures. Comparison with acute encephalitis/encephalopathy. Neurology 50:407.

98. Stavitsky, A. B., and J. Xianli. 2002. In vitro and in vivo regulation by macrophage migration inhibitory factor (MIF) of expression of MHC-II, costimulatory, adhesion, receptor, and cytokine molecules. Cell Immunol 217:95.

99. Mitchell, R. A., C. N. Metz, T. Peng, and R. Bucala. 1999. Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action. J Biol Chem 274:18100.

100. Jeschke, M. G., R. Einspanier, D. Klein, and K. W. Jauch. 2002. Insulin attenuates the systemic inflammatory response to thermal trauma. Mol Med 8:443.

101. Plaisance, V., N. Thompson, G. Niederhauser, J. A. Haefliger, P. Nicod, G. Waeber, and A. Abderrahmani. 2002. The mif gene is transcriptionally regulated by glucose in insulin-secreting cells. Biochem Biophys Res Commun 295:174.

102. Waeber, G., T. Calandra, C. Bonny, and R. Bucala. 1999. A role for the endocrine and pro-inflammatory mediator MIF in the control of insulin secretion during stress. Diabetes Metab Res Rev 15:47.

103. Hsueh, C., S. M. Jung, S. R. Shih, T. T. Kuo, W. J. Shieh, S. Zaki, T. Y. Lin, L. Y. Chang, H. C. Ning, and D. C. Yen. 2000. Acute encephalomyelitis during an outbreak of enterovirus type 71 infection in Taiwan: report of an autopsy case with pathologic, immunofluorescence, and molecular studies. Mod Pathol 13:1200.

104. Tracey, K. J. 2002. The inflammatory reflex. Nature 420:853.

105. Huang, F. L., S. L. Jan, P. Y. Chen, C. S. Chi, T. M. Wang, Y. C. Fu, C. R. Tsai, and Y. Chang. 2002. Left ventricular dysfunction in children with fulminant enterovirus 71 infection: an evaluation of the clinical course. Clin Infect Dis 34:1020.

106. Wessler, I., C. J. Kirkpatrick, and K. Racke. 1998. Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: expression and function in humans. Pharmacol Ther 77:59.

107. Yi, M., S. Kaneko, D. Y. Yu, and S. Murakami. 1997. Hepatitis C virus envelope proteins bind lactoferrin. J Virol 71:5997.

108. Shih, S. R., K. N. Tsai, Y. S. Li, C. C. Chueh, and E. C. Chan. 2003. Inhibition of enterovirus 71-induced apoptosis by allophycocyanin isolated from a blue-green alga Spirulina platensis. J Med Virol 70:119.

109. Yu, C. K., C. C. Chen, C. L. Chen, J. R. Wang, C. C. Liu, J. J. Yan, and I. J. Su. 2000. Neutralizing antibody provided protection against enterovirus type 71 lethal challenge in neonatal mice. J Biomed Sci 7:523.

110. Lin, Y. C., C. N. Wu, S. R. Shih, and M. S. Ho. 2002. Characterization of a Vero cell-adapted virulent strain of enterovirus 71 suitable for use as a vaccine candidate. Vaccine 20:2485.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2005-08-19起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2013-08-19起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw