金雀异黄素对大鼠异位子宫内膜的作用及相关机制
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摘要
目的：为探讨Gen在异位子宫内膜的作用及其机制,将不同剂量Gen处理于大鼠自体子宫内膜异位模型后,通过检测异位内膜细胞的凋亡；比较对异位内膜的雌激素受体α、β亚型分布变化；观察VEGF、CD34、MMP-9、TIMP-1、COX-2及Foxp3等指标的表达变化来研究不同剂量Gen对异位内膜细胞凋亡的诱导、对异位内膜侵袭、血管增生能力的影响和免疫耐受状态的影响。本研究不仅探讨了不同剂量Gen对异位内膜的作用并分析可能的相关机制,并且为开发Gen治疗子宫内膜异位症的药用价值提供有用的数据和理论依据。
方法：①大鼠子宫内膜异位模型的建立。选择6-8周龄的SD雌性大鼠,皮下注射乙烯雌酚以达到相同发情周期,通过手术将自体子宫内膜移植于腹壁筋膜层,注射17β-雌二醇3周后,观察并选择成功造膜大鼠。②给药方法和剂量的选择：对照组：花生油7.5ml/(kg.d)灌胃；治疗组：将Gen室温下用花生油配成混悬液,按7.5ml/(kg.d)灌胃,其中低剂量组Gen50mg/kg/d,中剂量组Gen150mg/kg/d,高剂量组Gen450mg/kg/d。③取材：每组用药共6周时间,末次给药24小时后,10%的水合氯醛麻醉,通过外科手术取出移植物,部分标本称湿重后冻存于液氮(待用RT-PCR),其余用10%中性福尔马林固定。④TUNEL法检测细胞凋亡,RT-PCR分析组织标本Bcl-2, Bax的mRNA表达。⑤ELISA法测定血清E2含量,免疫组织化法测定组织标本ERα、ERβ蛋白表达,RT-PCR法分析组织标本ER α、 ER β mRNA的表达。⑥SABC法检测组织标本VEGF、CD34、MMP-9、 TIMP-1、COX-2及Foxp3的表达。
结果：①移植物体积的变化：Gen给予后各组比较,移植物体积,随着剂量的增大趋于变小的趋势,高剂量组(D组)最明显,其抑制率有显著性差异(P<0.01),其它组间差异无统计学意义。②异位内膜组织凋亡细胞阳性表达情况：Gen高剂量组凋亡细胞指数明显高于其他组,差异有显著性意义(P<0.01),中剂量组凋亡指数高于低剂量组和对照组,但差异无显著性统计学意义。高剂量组较其他组相比Bcl-2mRNA表达下降、Bax mRNA表达上升,差异显著(P<0.01)。③随Gen剂量的增加,血清E2虽然有下降趋势,但统计结果无显著性差异(P>0.05)；高剂量Gen降低ERβ蛋白和ERβmRNA的表达,与各组间有显著性差异(P<0.01),但对ERα蛋白和ER a mRNA的表达影响不明显。④高剂量的Gen作用于大鼠异位内膜后明显降低VEGF、CD34及COX-2的表达(P<0.01)；降低MMP-9表达同时提升TIMP-1的表达(P<0.01),进而MMP-9/TIMP-1下降；Foxp3的表达明显下调(P<0.01)。
结论：Gen抑制大鼠自体移植的子宫内膜的生长与发育,且有剂量依赖效应。其具体机制为：①诱导异位内膜细胞的凋亡,可能与抑制Bcl-2、增强Bax的表达和活性有关；②影响异位内膜雌激素受体β亚型的表达,体现出ERβ拮抗剂的效应,暨抗雌激素效应；③通过下调VEGF、CD34、COX-2及MMP-9/TIMP-1的表达,抑制异位子宫内膜的侵袭和血管增生的生物活性；④通过抑制Foxp3的表达,降低异位内膜的免疫耐受状态,增强对异位内膜的免疫监视和免疫消除的能力。
Objective:To investigate biological effects of Gen on treatment of Endometriosis and its mechanism we treated various doses of Gen on experimentally induced endometriosis in a rat model. After treatment Gen, we observed ectopic endometrium growth, measured apoptosis induced-area and expression of apoptosis related indicators-Bcl2and Bax; we also observed the expression of estrogen receptor alpha and beta; to evaluate invasion ability and vascular proliferation ability on ectopic endometrium, we examined the expression of VEGF, CD34, MMP-9, TIMP-1, COX-2; lastly, through monitoring Foxp3, checked the effect of immune tolerance.
Methods:①Establishment of rat endometriosis model. The6-8weeks old female SD rats were selected and subcutaneous injected diethylstilbestrol to achieve the same estrous cycle, transplanted the autologous endometrial in the abdominal wall fascial layer, then injected17-beta-estradiol for3weeks.②Treatment method and dose selection. Control group was intragastric administratied7.5ml/(kg.d) of peanut oil; Treatment groups:Gen was suspended in7.5ml/(kg.d) of peanut oil and intragastric administrated:low-dose group, Gen50mg/kg/d; middle-dose group Gen150mg/kg/d; high-dose group Gen450mg/kg/d.③Medication persistence time and sampling. The medication time was6weeks. All animals were scarified24hours after last administration and recorded weight of wet tissue, some of specimen were cryopreserved in liquid nitrogen used for RT-PCR and the others fixed in10%neutral formalin for histological analysis.④We used TUNEL assay for detection apoptosis in ectopic endometrium after treatment, used RT-PCR and PCR technique for detection Bcl-2and Bax mRNA expression.⑤ELISA method was used for determination changes in serum E2, we also checked ER alpha, beta ER expression, both in mRNA level and protein level.⑥We performed SABC to detect tissue specimens of VEGF, CD34, MMP-9, TIMP-1, COX-2and Foxp3expression.
Results:①Change of graft size:As Gen dose increased, the eutopic endometrium volume tends to smaller. Spatially in the high dose group (D group) it was significantly decreased(P<0.01), while the other Gen groups showed no significant difference compare with control group.②Induction of cell apoptosis:Tissue from high dose Gen group showed higher apoptotic index than the other groups, significant difference (P<0.01), middle dose group apoptotic index higher than low dosage group and control group, but no significant differences. Compare with control group, Bcl-2mRNA expression was significantly up-regulated and Bax mRNA was significantly down-regulated in high dose group (P<0.01).③With the increasing doses of Gen, serum E2although showed a downward trend, but has no statistical significance (P>0.05); compared with other groups high dose Gen significantly reduces ERbeta protein and ER beta mRNA expression (P<0.01), but no effect on ERalpha.④High dose Gen can significantly decrease the expression of VEGF, CD34and COX-2(P<0.01); Also decrease the expression of MMP-9while increasing TIMP-1expression (P<0.01), High dose Gen significantly down-regulated Foxp3expression (P<0.01).
Conclusion:Gen can inhibit ectopic endometrium growth in our rat model and these inhibition effect expressed in a dose-dependent manner. Its mechanism as follows:①Induce apoptosis of ectopic endometrial cells through regulating apoptosis related gene expression and activity like Bcl-2and Bax;②Regulate expression of estrogen receptor subtypes:reflecting the beta ER antagonist effects and anti-estrogen effects;③Inhibit ectopic endometrium invasion and vascular proliferation activity through down-regulation of VEGF, CD34, COX-2and MMP-9/TIMP-1expression;④May decrease immune tolerance of ectopic endometrium or enhance immune surveillance and elimination by inhibiting Foxp3expression.
方法：①大鼠子宫内膜异位模型的建立。选择6-8周龄的SD雌性大鼠,皮下注射乙烯雌酚以达到相同发情周期,通过手术将自体子宫内膜移植于腹壁筋膜层,注射17β-雌二醇3周后,观察并选择成功造膜大鼠。②给药方法和剂量的选择：对照组：花生油7.5ml/(kg.d)灌胃；治疗组：将Gen室温下用花生油配成混悬液,按7.5ml/(kg.d)灌胃,其中低剂量组Gen50mg/kg/d,中剂量组Gen150mg/kg/d,高剂量组Gen450mg/kg/d。③取材：每组用药共6周时间,末次给药24小时后,10%的水合氯醛麻醉,通过外科手术取出移植物,部分标本称湿重后冻存于液氮(待用RT-PCR),其余用10%中性福尔马林固定。④TUNEL法检测细胞凋亡,RT-PCR分析组织标本Bcl-2, Bax的mRNA表达。⑤ELISA法测定血清E2含量,免疫组织化法测定组织标本ERα、ERβ蛋白表达,RT-PCR法分析组织标本ER α、 ER β mRNA的表达。⑥SABC法检测组织标本VEGF、CD34、MMP-9、 TIMP-1、COX-2及Foxp3的表达。
结果：①移植物体积的变化：Gen给予后各组比较,移植物体积,随着剂量的增大趋于变小的趋势,高剂量组(D组)最明显,其抑制率有显著性差异(P<0.01),其它组间差异无统计学意义。②异位内膜组织凋亡细胞阳性表达情况：Gen高剂量组凋亡细胞指数明显高于其他组,差异有显著性意义(P<0.01),中剂量组凋亡指数高于低剂量组和对照组,但差异无显著性统计学意义。高剂量组较其他组相比Bcl-2mRNA表达下降、Bax mRNA表达上升,差异显著(P<0.01)。③随Gen剂量的增加,血清E2虽然有下降趋势,但统计结果无显著性差异(P>0.05)；高剂量Gen降低ERβ蛋白和ERβmRNA的表达,与各组间有显著性差异(P<0.01),但对ERα蛋白和ER a mRNA的表达影响不明显。④高剂量的Gen作用于大鼠异位内膜后明显降低VEGF、CD34及COX-2的表达(P<0.01)；降低MMP-9表达同时提升TIMP-1的表达(P<0.01),进而MMP-9/TIMP-1下降；Foxp3的表达明显下调(P<0.01)。
结论：Gen抑制大鼠自体移植的子宫内膜的生长与发育,且有剂量依赖效应。其具体机制为：①诱导异位内膜细胞的凋亡,可能与抑制Bcl-2、增强Bax的表达和活性有关；②影响异位内膜雌激素受体β亚型的表达,体现出ERβ拮抗剂的效应,暨抗雌激素效应；③通过下调VEGF、CD34、COX-2及MMP-9/TIMP-1的表达,抑制异位子宫内膜的侵袭和血管增生的生物活性；④通过抑制Foxp3的表达,降低异位内膜的免疫耐受状态,增强对异位内膜的免疫监视和免疫消除的能力。
Objective:To investigate biological effects of Gen on treatment of Endometriosis and its mechanism we treated various doses of Gen on experimentally induced endometriosis in a rat model. After treatment Gen, we observed ectopic endometrium growth, measured apoptosis induced-area and expression of apoptosis related indicators-Bcl2and Bax; we also observed the expression of estrogen receptor alpha and beta; to evaluate invasion ability and vascular proliferation ability on ectopic endometrium, we examined the expression of VEGF, CD34, MMP-9, TIMP-1, COX-2; lastly, through monitoring Foxp3, checked the effect of immune tolerance.
Methods:①Establishment of rat endometriosis model. The6-8weeks old female SD rats were selected and subcutaneous injected diethylstilbestrol to achieve the same estrous cycle, transplanted the autologous endometrial in the abdominal wall fascial layer, then injected17-beta-estradiol for3weeks.②Treatment method and dose selection. Control group was intragastric administratied7.5ml/(kg.d) of peanut oil; Treatment groups:Gen was suspended in7.5ml/(kg.d) of peanut oil and intragastric administrated:low-dose group, Gen50mg/kg/d; middle-dose group Gen150mg/kg/d; high-dose group Gen450mg/kg/d.③Medication persistence time and sampling. The medication time was6weeks. All animals were scarified24hours after last administration and recorded weight of wet tissue, some of specimen were cryopreserved in liquid nitrogen used for RT-PCR and the others fixed in10%neutral formalin for histological analysis.④We used TUNEL assay for detection apoptosis in ectopic endometrium after treatment, used RT-PCR and PCR technique for detection Bcl-2and Bax mRNA expression.⑤ELISA method was used for determination changes in serum E2, we also checked ER alpha, beta ER expression, both in mRNA level and protein level.⑥We performed SABC to detect tissue specimens of VEGF, CD34, MMP-9, TIMP-1, COX-2and Foxp3expression.
Results:①Change of graft size:As Gen dose increased, the eutopic endometrium volume tends to smaller. Spatially in the high dose group (D group) it was significantly decreased(P<0.01), while the other Gen groups showed no significant difference compare with control group.②Induction of cell apoptosis:Tissue from high dose Gen group showed higher apoptotic index than the other groups, significant difference (P<0.01), middle dose group apoptotic index higher than low dosage group and control group, but no significant differences. Compare with control group, Bcl-2mRNA expression was significantly up-regulated and Bax mRNA was significantly down-regulated in high dose group (P<0.01).③With the increasing doses of Gen, serum E2although showed a downward trend, but has no statistical significance (P>0.05); compared with other groups high dose Gen significantly reduces ERbeta protein and ER beta mRNA expression (P<0.01), but no effect on ERalpha.④High dose Gen can significantly decrease the expression of VEGF, CD34and COX-2(P<0.01); Also decrease the expression of MMP-9while increasing TIMP-1expression (P<0.01), High dose Gen significantly down-regulated Foxp3expression (P<0.01).
Conclusion:Gen can inhibit ectopic endometrium growth in our rat model and these inhibition effect expressed in a dose-dependent manner. Its mechanism as follows:①Induce apoptosis of ectopic endometrial cells through regulating apoptosis related gene expression and activity like Bcl-2and Bax;②Regulate expression of estrogen receptor subtypes:reflecting the beta ER antagonist effects and anti-estrogen effects;③Inhibit ectopic endometrium invasion and vascular proliferation activity through down-regulation of VEGF, CD34, COX-2and MMP-9/TIMP-1expression;④May decrease immune tolerance of ectopic endometrium or enhance immune surveillance and elimination by inhibiting Foxp3expression.
引文
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