Effect of artesunate on acute rejection after small intestine transplantation in rats

doi:10.3969/j.issn.2095-4344.2014.05.018

Abstract

Abstract:

BACKGROUND: As the potent, specific immunosuppressants emerge, the survival rate after intestinal transplantation is improved to some extent. However, the adverse effects of immunosuppressants and expensive treatment costs are not tolerable for many patients. Therefore, it is clinically meaningful to choose traditional Chinese medicine which presents immunosuppressive effects. Artesunate has immune suppression effect, reduces acute rejection following small intestine transplantation, and improves the success rate of small intestine transplantation.

OBJECTIVE: To observe the effect and action mechanism of artesunate in acute rejection after small intestine transplantation in rats.

METHODS: Allogeneic small intestine transplantation models were established in the closed group of Sprague-Dawley rats and Wistar rats, and then were randomly divided into three groups, syngenic transplantation group (SD→SD), allogeneic transplantation group (Wistar→SD), and artesunate treatment group (Wistar→SD + artesunate 60 mg/kg per day, intraperitoneal injection).

RESULTS AND CONCLUSION: Rats in syngenic transplantation group survived for more than 10 days and they were all killed on day 10. The average survival of rats in allogeneic transplantation group and artesunate treatment group was respectively (6.73±0.58) days and (8.50±0.74) days, with significant differences between the two groups (P < 0.01). Histopathological examination showed that, there was no apparent rejection in syngenic transplantation group specimens, but mild, moderate and severe rejections in allogeneic transplantation group ondays 3, 5, 7. In treatment group, some specimens had mild rejection, but appeared relatively late to a low degree. Enzyme linked immunosorbent assay results revealed that, serum interleukin-2 and interferon-gamma expression levels in allogeneic transplantation group were significantly higher than other two groups after surgery (P < 0.01), serum interleukin-2 gene expression level in treatment group was also higher than syngenic transplantation group, but there was no significant difference (P > 0.05), serum interferon-gamma expression level in treatment group was higher than syngenic transplantation group (P < 0.05). Artesunate can inhibit acute rejection after rat small intestine transplantation, and its mechanism may be related to inhibition effect on the secretion and expression of interleukin-2, interferon-gamma and other cytokines.

中国组织工程研究杂志出版内容重点：肾移植；肝移植；移植；心脏移植；组织移植；皮肤移植；皮瓣移植；血管移植；器官移植；组织工程

全文链接：

Key words: organ transplantation, intestine, small, graft rejection, artemisia annua, interleukin-2, interferon-gamma

CLC Number:

R318

Yu Xiao-di, Wang Wei-zhong, Jiao Jie-ying, Zheng Jian-yong, Zhao Zheng-wei. Effect of artesunate on acute rejection after small intestine transplantation in rats[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(5): 761-766.

Figures/Tables 2

References

[1] 伍晓汀,黎介寿.改进技术的大鼠全小肠移植术[J].中华显微外科杂志,1999,22(1):48-50.

[2] 董光龙,李开宗,王为忠,等.双Cuff双造口大鼠异位小肠移植模型的建立[J].第四军医大学学报,2003,24(2):189.

[3] Rosemurgy AS, Schraut WH. Small bowel allografts. Sequence of histologic changes in acute and chronic rejection. Am J Surg. 1986;151(4):470-475.

[4] Schmid T, Oberhuber G, Körözsi G,et al. Histologic pattern of small bowel allograft rejection in the rat. Mucosal biopsies do not provide sufficient information. Gastroenterology. 1989; 96(6):1529-1532.

[5] 吴波,周晓军.小肠移植后急性排斥反应的病理诊断标准[J].肠外与肠内营养,2005,12(6):378-381.

[6] 夏穗生.临床移植医学[M].杭州:浙江科学技术出版社,1999: 438-442.

[7] 张汝芝,高玉祥.青蒿琥酯对Ⅰ~Ⅳ型变态反应的影响[J].中华皮肤科杂志,1998,31(6):368-372.

[8] 杨启超.青蒿素及其衍生物青蒿酯钠与青蒿醚的药理研究[J].广西医学,1984,6(6):292-294.

[9] 徐继红,章元沛.二氢青蒿素与青蒿琥酯的抗孕作用[J].药学学报,1996,31(9):657-659.

[10] Greenfeld K, Avraham R, Benish M,et al. Immune suppression while awaiting surgery and following it: dissociations between plasma cytokine levels, their induced production, and NK cell cytotoxicity. Brain Behav Immun. 2007;21(4):503-513.

[11] 封光华,张喜平,朱炜,等.小肠移植患者可溶性白介素2受体的早期变化(附一例报道)[J].胃肠病学和肝病学杂志,2006,15(1): 98-99.

[12] Williams JG, Jurkovich GJ, Maier RV. Interferon-gamma: a key immunoregulatory lymphokine. J Surg Res. 1993;54(1): 79-93.

[13] 育柳英,林培英,张丹,等.青蒿琥酯对小鼠肝癌及S180实体瘤的抑制作用[J].实用癌症杂志,2001,16(3):245-247.

[14] 林培英,冯昭明,潘竟锵.青蒿琥酯对小鼠免疫功能的影响[J].中国药理学报,1995,16(5):441-443.

[15] Khan NU, Fildes JE, Al-Aloul M, et al. Increased serum concentrations of Th1 chemokines are associated with acute rejection following heart transplantation. The Journal of Heart and Lung Transplantation.2007;26(2):194.

[16] Middleton SJ, Jamieson NV. The current status of small bowel transplantation in the UK and internationally. Gut. 2005;54(11): 1650-1657.

[17] Matsuura T, Taguchi T, Hayashida M,et al. Relationship between real-time monitoring of the graft motility and mucosal histology in swine intestinal transplantation.Transplant Proc. 2006;38(6):1851-1852.

[18] Tocci MJ, Matkovich DA, Collier KA, et al. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol. 1989; 143: 718-726.

[19] Greenfeld K, Avraham R, Benish M, et al. Immune suppression while awaiting surgery and following it: Dissociations between plasma cytokine levels, their induced production, and NK cell cytotoxicity . Brain Behav Immun. 2007;21(4):503-513.

[20] 金伯泉.细胞和分子免疫学[M].2版.北京:科学出版社,2001: 396-411.

[21] Ziarkiewicz-Wróblewska B, Górnicka B, O?dakowska U,et al. Plasmacytic hyperplasia--the early form of posttransplant lymphoproliferative disorder--with atypical morphology and clinical course in patient after liver transplantation: a case report. Transplant Proc. 2003; 35(6):2320-2322.

[22] Robert CD, Lacaille F, Canioni D,et al. EBV-negative lymphoproliferative disease with hyper-IgA, in a child with combined liver and small bowel transplantation. Pediatr Transplant. 2004;8(3):305-307.

[23] 李泽林,杨立新,刘菊福,等.青蒿酯钠致畸作用的研究[J].中药通报,1988,13(4) :234-236.

[24] Singh NP, Lai H. Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci. 2001;70(1):49-56.

[25] Woerdenbag HJ, Moskal TA, Pras N,et al. Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J Nat Prod. 1993;56(6):849-856.

[26] 宁殿玺,徐在海,滕翕和.青蒿酯钠静脉注射对犬的亚急性毒性[J].中国药理学与毒理学杂志,1987,1(1):135-136.

[27] Dayan AD. Neurotoxicity and artemisinin compounds do the observations in animals justify limitation of clinical use. Med Trop (Mars). 1998;58(3 Suppl):32-37.

[28] Gorczynski RM, Alexander C, Bessler W,et al. An alteration in the levels of populations of CD4+ Treg is in part responsible for altered cytokine production by cells of aged mice which follows injection with a fetal liver extract. Immunol Lett. 2007; 109(2):101-112.

[29] Gorczynski RM, Alexander C, Bessler W,et al.An alteration in the levels of populations of CD4+ Treg is in part responsible for altered cytokine production by cells of aged mice which follows injection with a fetal liver extract.Immunol Lett. 2007; 109(2):101-112.

[30] 周平,高玉祥.青蒿琥酯对小鼠免疫功能的影响[J].蚌埠医学院学报,1996,21(1):5-8.

[31] Khan NU, Fildes JE, Al-Aloul M, et al. Increased serum concentrations of Th1 chemokines are associated with acute rejection following heart transplantation.J Heart Lung Transplantation. 2007;26(2):194.

[32] Nakashima H. Membranous nephropathy is developed under Th2 environment in chronic graft-versus-host disease. Med Hypotheses. 2007;69(4):787-791.

[33] 金慧玲,高玉祥.青蒿琥酯对豚鼠表皮郎格罕细胞的影响[J].蚌埠医学院学报,1993,18(4) :225-227.

[34] 张利群,窦肇华.大鼠小肠移植急性排斥反应中IL-2表达的研究[J].临沂医学专科学校学报,2004,26(3):161-162.

[35] Dekel B, Böcher WO, Marcus H,et al. Acute cellular rejection of human renal tissue by adoptive transfer of allogeneic human peripheral blood mononuclear cells into chimeric rats: sequential gene expression of cytokines, chemokines and cytolytic effector molecules, and their regulation by CTLA-4-Ig. Int Immunol. 1999;11(10):1673-1683.

[36] Steiger JU, Nickerson PW, Hermle M,et al. Interferon-gamma receptor signaling is not required in the effector phase of the alloimmune response. Transplantation. 1998;65(12): 1649-1652.

[37] 周平,高玉祥.青蒿琥酯对NK细胞活性及ADCC 活性的影响[J].蚌埠医学院学报,1995,20(6):363-365.

[38] Newell KA, He G, Guo Z,et al. Cutting edge: blockade of the CD28/B7 costimulatory pathway inhibits intestinal allograft rejection mediated by CD4+ but not CD8+ T cells.J Immunol. 1999;163(5):2358-2362.

[39] Valujskikh A, Heeger PS. CD4+ T cells responsive through the indirect pathway can mediate skin graft rejection in the absence of interferon-gamma.Transplantation. 2000;69(5): 1016-1019.

[40] Su GL, Walgenbach KJ, Heeckt PH,et al. Increased expression of interferon-gamma in a rat model of chronic intestinal allograft rejection.Transplantation. 1996; 62(2): 242-248.

[41] 莫正魁,李立,王建忠.青蒿素对小鼠迟发型超敏反应的免疫抑制作用[J].昆明医学院学报, 2005,26(4): 55-59.

[42] 林培英,张丹,肖柳英,等.青蒿素、青蒿酯和蒿甲醚对抑制性T细胞的作用[J].广州医药,1998,29(1):37-39.

[43] 余其斌,金慧玲.青蒿琥酯治疗系统性红斑狼疮30例临床观察[J]. 蚌埠医学院学报,1996,21(3):173-174.

[44] 金慧玲,肖玉周,高玉祥,等.青蒿琥酯对大鼠皮肤移植排斥反应的影响[J].蚌埠医学院学报,1997,22(3):152-153.

[45] Takeuchi T, Lowry RP, Konieczny B. Heart allografts in murine systems. The differential activation of Th2-like effector cells in peripheral tolerance. Transplantation. 1992; 53(6):1281-1294.

[46] Dallman MJ, Larsen CP, Morris PJ. Cytokine gene transcription in vascularised organ grafts: analysis using semiquantitative polymerase chain reaction. J Exp Med. 1991;174(2):493-496.

[47] Hitoshi Nakashima. Membranous nephropathy is developed under Th2 environment in chronic graft-versus-host disease. Medical Hypotheses, 2007, 30: 231-235.

[48] 郭尧,吴玲娟,徐潘生,等.大白鼠长期服用青蒿琥酯的安全性评估[J].中国血吸虫病防治杂志,2000,12(1):27-29.

[49] 张俊才.健康人对青蒿琥酯片的耐受性和不良反应[J].新药与临床,1992,11(2):70-72.

[50] 刘旭.抗疟药青蒿琥酯的研究[J].药学进展,1999,23:47-50.

[51] 陈重阳,袁模军,唐国权.青蒿琥酯对小鼠实验性肝损伤的保护作用[J].中国药理学通报,1990,6(6):382.