清热化瘀法对子宫内膜异位症患者血管生成机制的影响
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摘要
目的:比较以清热化瘀法为主的中药与西药醋酸曲普瑞林(注射用GnRHa)治疗腹腔镜术后子宫内膜异位症(EMs)患者的临床疗效差异,探讨外周血中血管内皮生长因子(VEGF)、血管内皮生长因子-受体1(VEGF-R_1)、血管内皮生长因子-受体2(VEGF-R_2)、前列腺素E2(PGE_2)和环氧化酶2(COX_2)与EMs发病的相关性,为本病的中医药防治提供依据。方法:选择90例EMs患者及输卵管炎性疾病患者,分为中药组、西药组和对照组,每组30例。中药组术后口服清热化瘀中药汤剂,连续治疗3个月经周期;西药组于术后第1次月经来潮第1～5天内皮下注射醋酸曲普瑞林(GnRHa),每4周1次,连用3月;对照组为输卵管炎性疾病患者,术后不使用药物。ELISA法测定患者外周静脉血中VEGF、VEGF-R_1、VEGF-R_2、PGE2和COX_2的浓度,探讨EMs的发病机理。结果:外周静脉血中VEGF、VEGF-R_1、VEGF-R_2浓度中药组、西药组均高于对照组,差异有统计学意义(P<0.05);PGE_2和COX_2浓度中药组、西药组与对照组比较,差异无统计学意义(P>0.05);外周静脉血中VEGF、VEGF-R_1、VEGF-R_2、PGE_2、COX_2浓度治疗前后3组组内比较差异有统计学意义(P<0.05);治疗后中药组、西药组与对照组比较,差异也有统计学意义(P<0.05);治疗后中药组与西药组比较,差异无统计学意义(P>0.05)。结论:外周静脉血中VEGF、VEGF-R_1和VEGF-R_2的含量在一定程度上能够反映EMs的发生及发展进程,清热化瘀法可能是通过降低血管内皮生长因子及其受体的含量,达到治疗内异症的目的。
Objective:To compare clinical effects of herbs of heat-clearing stasis-eliminating and Western medicine triptorelin acetate injection(GnRHa for injection) in treating endometriosis(EMs) after laparoscopic surgery, and survey the correlation between the incidence of EMs and VEGF, VEGF-R_1, VEGF-R_2, PGE_2 and COX_2 in peripheral blood, to provide the reference for TCM prevention and treatment of EMs. Methods: Ninety patients with EMs and salpingitis disease were screened and assigned to herbal group, Western medicine group and the control group, 30 cases each group. The herbal group took the decoction of heat-clearing stasis-eliminating orally after the operation for three menstrual cycles consecutively; the group of Western medicine accepted hypodermic injection of GnRHa from the first day to the fifth day of the first period after the surgery, once each four weeks, for three months consecutively; the patients with salpingitis disease in the control group didn′t use the medicine after the surgery. The pathogenesis of EMs was discussed, and the concentrations of VEGF, VEGF-R_1, VEGF-R_2, PGE_2 and COX_2 in peripheral blood were detected using ELISA method. Results: The herbal group and Western medicine group were higher than the control group in the concentrations of VEGF, VEGF-R_1 and VEGF-R_2 in peripheral blood, and the difference had statistical meaning(P <0.05); the difference had no statistical meaning when the herbal group and Western medicine group were compared with the control group in the concentrations of PGE_2 and COX-2(P>0.05); the difference had statistical meaning in the comparisons of the concentrations of VEGF, VEGF-R_1,VEGF-R_2, PGE_2 and COX_2 in peripheral blood before and after treating within three groups before and after treating(P<0.05); the difference had statistical meaning when the herbal group and Western medicine group were compared with the control group after treating(P<0.05); the difference had no statistical meaning when the herbal group was compared with Western medicine group after treating(P>0.05). Conclusion: The contents of VEGF, VEGF-R_1 and VEGF-R_2 in peripheral blood could reflect the incidence and the developmental progress of EMs to a certain degree,heat-clearing stasis-eliminating method could achieve the aim of treating EMs through inhibiting the contents of lowering vascular endothelial growth factor and its receptor.
Objective:To compare clinical effects of herbs of heat-clearing stasis-eliminating and Western medicine triptorelin acetate injection(GnRHa for injection) in treating endometriosis(EMs) after laparoscopic surgery, and survey the correlation between the incidence of EMs and VEGF, VEGF-R_1, VEGF-R_2, PGE_2 and COX_2 in peripheral blood, to provide the reference for TCM prevention and treatment of EMs. Methods: Ninety patients with EMs and salpingitis disease were screened and assigned to herbal group, Western medicine group and the control group, 30 cases each group. The herbal group took the decoction of heat-clearing stasis-eliminating orally after the operation for three menstrual cycles consecutively; the group of Western medicine accepted hypodermic injection of GnRHa from the first day to the fifth day of the first period after the surgery, once each four weeks, for three months consecutively; the patients with salpingitis disease in the control group didn′t use the medicine after the surgery. The pathogenesis of EMs was discussed, and the concentrations of VEGF, VEGF-R_1, VEGF-R_2, PGE_2 and COX_2 in peripheral blood were detected using ELISA method. Results: The herbal group and Western medicine group were higher than the control group in the concentrations of VEGF, VEGF-R_1 and VEGF-R_2 in peripheral blood, and the difference had statistical meaning(P <0.05); the difference had no statistical meaning when the herbal group and Western medicine group were compared with the control group in the concentrations of PGE_2 and COX-2(P>0.05); the difference had statistical meaning in the comparisons of the concentrations of VEGF, VEGF-R_1,VEGF-R_2, PGE_2 and COX_2 in peripheral blood before and after treating within three groups before and after treating(P<0.05); the difference had statistical meaning when the herbal group and Western medicine group were compared with the control group after treating(P<0.05); the difference had no statistical meaning when the herbal group was compared with Western medicine group after treating(P>0.05). Conclusion: The contents of VEGF, VEGF-R_1 and VEGF-R_2 in peripheral blood could reflect the incidence and the developmental progress of EMs to a certain degree,heat-clearing stasis-eliminating method could achieve the aim of treating EMs through inhibiting the contents of lowering vascular endothelial growth factor and its receptor.
引文
[1]Sekizawa A,Amemiya S,Otsuka J,et al.Malignant transformation of endometriosis:application of laser microdissection for analysis of genetic alterations according to pathological changes[J].Med Electron Microsc,2004,37(2):97-100.
[2]Guo SW.Recurrence of endometriosis and its control[J].Hum Reprod Update,2009,15(4):441-461.
[3]Mosser DM."The many faces of macrophage activation."[In eng].JLeukoc Biol 2003,73,(2)::209-212.
[4]庄梦斐,张婷婷,孙兆贵,等.清热化瘀法对子宫内膜异位症大鼠血管生成和炎症相关因子表达的影响[J].中华中医药杂志,2016,31(5):1595-1599.
[5]中华医学会妇产科学分会子宫内膜异位症协作组.子宫内膜异位症的诊断与治疗规范[J].中华妇产科杂志,2007,42(9):645-648.
[6]中国中西医结合学会妇产科专业委员会.子宫内膜异位症、妊娠高血压综合征及女性不孕症的中西医结合诊疗标准[J].中西医结合杂志,1991,11(6):376-379.
[7]中华中医药学会.中医妇科常见病诊疗指南[M].北京:中国中医药出版社,2012:120-123.
[8]杨丽丽.内异止痛汤对EMs大鼠关键基因的筛选及炎症相关机制研究[D].哈尔滨:黑龙江中医药大学,2015.
[9]尹利荣,王宇全,米淑玲,等.子宫内膜异位症中单核-巨噬细胞分泌VEGF水平的研究[J].天津医药,2004,32(9):532-534.
[10]曹阳,朱焰,秦保峰,等.红藤颗粒剂对子宫内膜异位症大鼠异位内膜黏附分子相关基因表达及血管内皮生长因子mR-NA表达的影响[J].生殖与避孕,2011.31(2):73-81.
[11]李少荣,胡晓继.血管内皮生长因子基因多态性与子宫内膜异位症[J].华南国防医学杂志,2016.30(1):75-78.
[12]Fang F,Gong L,Wang X,et al.The association between vascular endothelial growth factor(VEGF)+405g>Cgenetic polymorphism and endometriosis[J].Exp Biol Med(Maywood),2015,240(9):1177-82.
[13]Takahash S.Vascular end othelial growth factor(VEGF),VEGF receptors and their Inhibitors for antiangiogenic tumor therapy[J].Biol Pharm Bull,2011,34(12):1785-1788.
[14]Carmeliet P.VEGF as a key mediator of angiogenesis in cancer[J].Oncology,2005,69(3):4-10.
[15]Zhang Z,Neiva KG,Lingen MW,et a1,VEGF-dependent tumor angiogenesis requires the inverse and reciprocal regulation of VEGFR1and VEGFR2[J].Cell Death Differ,2010,17(3):499-512.
[16]Cho S,Choi YS,Jeon YE,et a1,Expression of vascular endothelial growth factor(VEGF)and its soluble receptor-1 in endometriosis[J].Microvasc Res,2012.83(2):237-242.
[17]Ricci AG,Olivares CN,Bilotas MA,eta1,Effectof vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis[J].Reprod Sci,2011,18(7):614-622.
[18]Shibuya M.Differentialrolesofvascularendothelialgrowthfactor receptor-1 and receptor-2 in angiogenesis[J].J Biochem Mol Biol,2006,39(5):469-678.
[19]曹阳,张婷婷,谢淑武,等.红藤颗粒剂对大鼠异位子宫内膜血管内皮生长因子及其受体胎肝激酶-1表达的影响[J].中西医结合学报,2009,7(4):360-365.
[20]Timms KL,Zimmer RL,Ricke EA,et al,Endometriotic haptoglobin binds to peritneal macrophages and alters their function in women with endometriosis[J].Fertil Steril,2002,78(4):810-819.
[21]Wu MH,Chuang PC,Lin YJ,et al,Suppression of annexin A2by prostaglandin E2 impairs phagocytic ability of peritoneal macrophages in women with endometriosis[J].Hum Reprod,2013,28(4):1045-1058.
[22]Deura I,Harada T,Taniguchi F,et al,Reduction of estrogen production by interleukin-6 in a human granulosa tumor cell line may have implications for endometriosis-associated infertility[J].Fertil Steril,2005,83(1):1086-1092.
[23]Hsu CC,Lu CW,Huang BM,et al,Cyclic adenosine 3′,5′-monophosphate response element-binding protein and CCAAT/enhancer-bindingproteinmediateprostaglandin E2-induced steroidogenic acute regulatory protein expression in endometriotic stromal cells[J].Am J Pathol,2008,173(2):433-441.
[24]Du YB,Gao MZ,Shi Y,et al.Endocrine and inflammatory factors and endometriosis-associated infertility in assisted reproduction techniques[J].Arch Gynecol Obstet,2013,287(1):123-130.
[25]姚红梅,郭静,石秀玲.VEGF CD44v6 MMP-9在子宫内膜异位症组织中的表达及临床意义[J].济宁医学院学报,2013,36(2):124-126,132.
[26]张婷婷,陈麒,朱抗美,等.中药“红藤方”对子宫内膜异位症模型大鼠异位内膜的形态学影响[J].生殖与避孕,2005,25(12):716-719.
[27]刘津翚,张婷婷,束兰娣,等.红藤方对体外培养的大鼠子宫内膜细胞生长特性的影响[J].天津中医药,2009,26(4):329-331.
[28]张婷婷,刘津翚,束兰娣,等.红藤方对子宫内膜异位症大鼠MMP-9和MMP-2蛋白表达的干预作用[J].上海中医药大学学报,2005,19(4):48-51.
[2]Guo SW.Recurrence of endometriosis and its control[J].Hum Reprod Update,2009,15(4):441-461.
[3]Mosser DM."The many faces of macrophage activation."[In eng].JLeukoc Biol 2003,73,(2)::209-212.
[4]庄梦斐,张婷婷,孙兆贵,等.清热化瘀法对子宫内膜异位症大鼠血管生成和炎症相关因子表达的影响[J].中华中医药杂志,2016,31(5):1595-1599.
[5]中华医学会妇产科学分会子宫内膜异位症协作组.子宫内膜异位症的诊断与治疗规范[J].中华妇产科杂志,2007,42(9):645-648.
[6]中国中西医结合学会妇产科专业委员会.子宫内膜异位症、妊娠高血压综合征及女性不孕症的中西医结合诊疗标准[J].中西医结合杂志,1991,11(6):376-379.
[7]中华中医药学会.中医妇科常见病诊疗指南[M].北京:中国中医药出版社,2012:120-123.
[8]杨丽丽.内异止痛汤对EMs大鼠关键基因的筛选及炎症相关机制研究[D].哈尔滨:黑龙江中医药大学,2015.
[9]尹利荣,王宇全,米淑玲,等.子宫内膜异位症中单核-巨噬细胞分泌VEGF水平的研究[J].天津医药,2004,32(9):532-534.
[10]曹阳,朱焰,秦保峰,等.红藤颗粒剂对子宫内膜异位症大鼠异位内膜黏附分子相关基因表达及血管内皮生长因子mR-NA表达的影响[J].生殖与避孕,2011.31(2):73-81.
[11]李少荣,胡晓继.血管内皮生长因子基因多态性与子宫内膜异位症[J].华南国防医学杂志,2016.30(1):75-78.
[12]Fang F,Gong L,Wang X,et al.The association between vascular endothelial growth factor(VEGF)+405g>Cgenetic polymorphism and endometriosis[J].Exp Biol Med(Maywood),2015,240(9):1177-82.
[13]Takahash S.Vascular end othelial growth factor(VEGF),VEGF receptors and their Inhibitors for antiangiogenic tumor therapy[J].Biol Pharm Bull,2011,34(12):1785-1788.
[14]Carmeliet P.VEGF as a key mediator of angiogenesis in cancer[J].Oncology,2005,69(3):4-10.
[15]Zhang Z,Neiva KG,Lingen MW,et a1,VEGF-dependent tumor angiogenesis requires the inverse and reciprocal regulation of VEGFR1and VEGFR2[J].Cell Death Differ,2010,17(3):499-512.
[16]Cho S,Choi YS,Jeon YE,et a1,Expression of vascular endothelial growth factor(VEGF)and its soluble receptor-1 in endometriosis[J].Microvasc Res,2012.83(2):237-242.
[17]Ricci AG,Olivares CN,Bilotas MA,eta1,Effectof vascular endothelial growth factor inhibition on endometrial implant development in a murine model of endometriosis[J].Reprod Sci,2011,18(7):614-622.
[18]Shibuya M.Differentialrolesofvascularendothelialgrowthfactor receptor-1 and receptor-2 in angiogenesis[J].J Biochem Mol Biol,2006,39(5):469-678.
[19]曹阳,张婷婷,谢淑武,等.红藤颗粒剂对大鼠异位子宫内膜血管内皮生长因子及其受体胎肝激酶-1表达的影响[J].中西医结合学报,2009,7(4):360-365.
[20]Timms KL,Zimmer RL,Ricke EA,et al,Endometriotic haptoglobin binds to peritneal macrophages and alters their function in women with endometriosis[J].Fertil Steril,2002,78(4):810-819.
[21]Wu MH,Chuang PC,Lin YJ,et al,Suppression of annexin A2by prostaglandin E2 impairs phagocytic ability of peritoneal macrophages in women with endometriosis[J].Hum Reprod,2013,28(4):1045-1058.
[22]Deura I,Harada T,Taniguchi F,et al,Reduction of estrogen production by interleukin-6 in a human granulosa tumor cell line may have implications for endometriosis-associated infertility[J].Fertil Steril,2005,83(1):1086-1092.
[23]Hsu CC,Lu CW,Huang BM,et al,Cyclic adenosine 3′,5′-monophosphate response element-binding protein and CCAAT/enhancer-bindingproteinmediateprostaglandin E2-induced steroidogenic acute regulatory protein expression in endometriotic stromal cells[J].Am J Pathol,2008,173(2):433-441.
[24]Du YB,Gao MZ,Shi Y,et al.Endocrine and inflammatory factors and endometriosis-associated infertility in assisted reproduction techniques[J].Arch Gynecol Obstet,2013,287(1):123-130.
[25]姚红梅,郭静,石秀玲.VEGF CD44v6 MMP-9在子宫内膜异位症组织中的表达及临床意义[J].济宁医学院学报,2013,36(2):124-126,132.
[26]张婷婷,陈麒,朱抗美,等.中药“红藤方”对子宫内膜异位症模型大鼠异位内膜的形态学影响[J].生殖与避孕,2005,25(12):716-719.
[27]刘津翚,张婷婷,束兰娣,等.红藤方对体外培养的大鼠子宫内膜细胞生长特性的影响[J].天津中医药,2009,26(4):329-331.
[28]张婷婷,刘津翚,束兰娣,等.红藤方对子宫内膜异位症大鼠MMP-9和MMP-2蛋白表达的干预作用[J].上海中医药大学学报,2005,19(4):48-51.
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