Effect of dienogest in improvement of endometriosis and its mechanism
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摘要:目的
探讨地诺孕素缓解子宫内膜异位症(EMs)疼痛和炎症的作用及对脑源性神经营养因子(BDNF)/原肌球蛋白受体激酶B(TrkB)、核因子-κB(NF-κB)/NOD样受体热蛋白结构域蛋白3(NLRP3)炎症通路的影响。
方法采用同种异体移植法构建EMs大鼠模型, 并随机分为假手术组(n=16)、模型组(n=16)、地诺孕素低剂量组(n=16)、地诺孕素中剂量组(n=16)和地诺孕素高剂量组(n=16)。治疗7 d后，记录大鼠EMs模型的种植体积和扭动反应频率。采用酶联免疫吸附试验法、逆转录聚合酶链反应和蛋白质免疫印迹法分别检测大鼠EMs模型中血管内皮生长因子(VEGF)、诱导型一氧化氮合酶(iNOS)、白细胞介素(IL)-6、IL-1β和肿瘤坏死因子(TNF)-α的表达，并检测血清BDNF、TrkB、NF-κB和NLRP3的表达。
结果与模型组比较，地诺孕素可减小EMs的异位子宫内膜体积和减少扭动反应，差异有统计学意义(P < 0.05)。与模型组比较，地诺孕素可降低EMs模型中VEGF、iNOS、IL6、IL-1β和TNF-α的表达，差异有统计学意义(P < 0.05)。与模型组比较，地诺孕素可降低异位子宫内膜中BDNF、TrkB、NF-κB和NLRP3的表达，差异有统计学意义(P < 0.05)。
结论地诺孕素可缓解EMs相关的痛经及炎症，其作用机制可能部分通过BDNF/TrkB通路及NF-κB/NLRP3通路介导。
Abstract:ObjectiveTo investigate the effects of dienogest on pain relief and inflammation in endometriosis (EMs), as well as its impact on the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) and nuclear factor kappa-B (NF-κB)/NOD-like receptor protein 3 (NLRP3) inflammatory pathways.
MethodsAn allograft method was used to establish an EMs rat model. The rats were randomly divided into sham-operated group (n=16), model group (n=16), low-dose dienogest group (n=16), medium-dose dienogest group (n=16) and high-dose dienogest group (n=16). After 7 days of treatment, the implantation volume and writhing response frequency were recorded. Enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction and Western blotting were employed to measure the expression levels of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α in the EMs rat models. Serum levels of BDNF, TrkB, NF-κB and NLRP3 were detected.
ResultsCompared with model group, dinorgestrel significantly reduced ectopic endometrial volume and torsion response of EMs (P < 0.05). Compared with model group, dinorgestrel significantly decreased the expression of VEGF, iNOS, IL6, IL-1β and TNF-α in EMs model (P < 0.05). In addition, compared with model group, dienogest significantly decreased the expressions of BDNF, TrkB, NF-κB and NLRP3 in ectopic endometrium (P < 0.05).
ConclusionDinorgestrel can relieve EMS-related dysmenorrhea and inflammation, and its mechanism of action may be partly mediated by BDNF/TrkB pathway and NF-κB/NLRP3 pathway.
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表 1 各组大鼠腹部扭动的扭动频率、持续时间和扭动潜伏期
组别 n 腹部扭动的持续时间/s 扭动潜伏期/min 扭动频率/(N/30 min) 假手术组 6 4.46±0.62 7.12±0.62 18.21±1.67 模型组 6 11.38±2.05* 2.31±0.17* 45.52±2.86* 地诺孕素低剂量组 6 9.68±2.64# 4.62±1.13# 38.52±2.35# 地诺孕素中剂量组 6 7.31±2.49# 6.93±1.26## 26.57±2.41# 地诺孕素高剂量组 6 4.34±1.27# 13.81±1.38### 16.36±1.98# 与假手术组比较, * P < 0.05; 与模型组比较, #P < 0.05, ##P < 0.01, ###P < 0.001。 
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表 2 各组大鼠腹膜液中的VEGF水平(x±s) pg/mL
组别 n VEGF水平 假手术组 6 9.17±0.27 模型组 6 50.34±4.19* 地诺孕素低剂量组 6 34.39±3.15# 地诺孕素中剂量组 6 26.67±3.29# 地诺孕素高剂量组 6 19.42±2.56# VEGF: 血管内皮生长因子。与假手术组比较, * P < 0.05; 与模型组比较, #P < 0.05。
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表 3 各组大鼠腹膜液中的VEGF mRNA水平(x±s)
组别 n VEGF mRNA水平 假手术组 6 1.00±0.09 模型组 6 3.29±0.24* 地诺孕素低剂量组 6 2.82±0.35# 地诺孕素中剂量组 6 2.26±0.38# 地诺孕素高剂量组 6 1.94±0.52# 与假手术组比较, * P < 0.05; 与模型组比较, #P < 0.05。
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表 4 各组大鼠异位子宫内膜体积(x±s)
mm3 组别 n 异位子宫内膜体积 假手术组 6 0 模型组 6 121.87±18.21* 地诺孕素低剂量组 6 92.25±8.34# 地诺孕素中剂量组 6 62.29±6.15# 地诺孕素高剂量组 6 41.57±3.28# 与假手术组比较, * P < 0.05; 与模型组比较, #P < 0.05。
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表 5 各组大鼠 iNOS、IL-6、IL-1β 和TNF-α的mRNA表达水平(x±s)
组别 n iNOS mRNA IL-6 mRNA IL-1β mRNA TNF-α mRNA 假手术组 6 1.00±0.11 1.00±0.10 1.00±0.06 1.00±0.08 模型组 6 2.82±0.39* 3.63±0.17* 1.73±0.13* 2.19±0.31* 地诺孕素低剂量组 6 2.23±0.31# 2.82±0.31# 1.48±0.29# 1.82±0.28* 地诺孕素中剂量组 6 1.97±0.19# 2.11±0.21# 1.29±0.24* 1.51±0.26* 地诺孕素高剂量组 6 1.52±0.27# 1.72±0.16# 1.13±0.32# 1.31±0.23* iNOS: 诱导型一氧化氮合酶; IL-6 : 白细胞介素-6; IL-1β : 白细胞介素-1β; TNF-α: 肿瘤坏死因子-α。与假手术组比较, * P < 0.05; 与模型组比较, #P < 0.05。
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表 6 各组大鼠血清和腹腔液中BDNF的分泌水平(x±s)
pg/mL 组别 n 血清BDNF 腹腔液BDNF 假手术组 6 1 421.23±110.24 8.94±0.28 模型组 6 1 729.81±201.36* 42.13±2.17* 地诺孕素低剂量组 6 1 625.26±108.35# 28.24±2.23* 地诺孕素中剂量组 6 1 589.25±143.22# 19.28±3.26* 地诺孕素高剂量组 6 1 498.21±168.25# 15.57±1.13* BDNF: 脑源性神经营养因子。与假手术组比较, * P < 0.05; 与模型组比较, #P < 0.05。
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