ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model
ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model
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DOI：
10.1016/j.ajog.2014.01.040
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发表时间：
2014-06-01
影响因子：
9.8
通讯作者：
Liu, Fenghua
中科院分区：
文献类型：
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作者：
Wang, Yifeng;Lin, Min;Liu, Fenghua
目的：蛋白酶激活受体2在子宫内膜异位症的发病机制中发挥重要作用。我们在非侵入性荧光小鼠模型中研究了蛋白酶激活受体 2 拮抗剂 ENMD-1068 对子宫内膜异位症发展的影响。研究设计：在裸鼠中创建了表达红色荧光蛋白的人类子宫内膜异位症异种移植模型。子宫内膜异位诱导后，每天给小鼠腹膜内注射25mg/kg或50mg/kg ENMD-1068或200μL载体对照，持续5天。然后对小鼠中出现的子宫内膜异位病变进行计数、测量和收集。通过酶联免疫吸附测定评估病变处白细胞介素6和单核细胞趋化蛋白1的产生，并通过免疫组织化学分析评估核因子κB的激活和血管内皮生长因子的表达。通过免疫组织化学分别评估 Ki-67 和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记的细胞增殖和凋亡。 结果：ENMD-1068 剂量依赖性地抑制子宫内膜异位病变的发展 (P < .05)，对治疗小鼠的各个器官没有明显的毒性。一致地，ENMD-1068 剂量依赖性地抑制病灶中白细胞介素 6 和核因子 kappa B 的表达 (P < .05) 和细胞增殖 (P < .05)，并增加凋亡细胞的百分比 (P < .05)。 ENMD-1068 降低了病灶中单核细胞趋化蛋白-1 和血管内皮生长因子的水平 (P < .05)，但不是以剂量依赖性方式。 结论：我们的研究表明 ENMD-1068 可有效抑制子宫内膜异位症的生长，这可能归因于该药物的抗血管生成和抗炎活性。
OBJECTIVE: Protease-activated receptor 2 plays an important role in the pathogenesis of endometriosis. We studied the effect of ENMD-1068, a protease-activated receptor 2 antagonist, on the development of endometriosis in a noninvasive fluorescent mouse model.STUDY DESIGN: A red fluorescent protein-expressing xenograft model of human endometriosis was created in nude mice. After endometriosis induction, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 mu L of the vehicle control daily for 5 days. The endometriotic lesions that developed in the mice were then counted, measured, and collected. The lesions were assessed for the production of interleukin 6 and monocyte chemotactic protein-1 by enzym-linked immunosorbent assays and evaluated for the activation of nuclear factor-kappa B and the expression of vascular endothelial growth factor by immunohistochemical analyses. Cell proliferation and apoptosis were assessed by immunohistochemistry for Ki-67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, respectively.RESULTS: ENMD-1068 dose-dependently inhibited the development of endometriotic lesions (P < .05) without apparent toxicity to various organs of the treated mice. Consistently, ENMD-1068 dose-dependently inhibited the expression of interleukin 6 and nuclear factor-kappa B (P < .05) and cell proliferation (P < .05) in the lesions, as well as increased the percentage of apoptotic cells (P < .05). ENMD-1068 reduced the levels of monocyte chemotactic protein-1 and vascular endothelial growth factor in the lesions (P < .05), but not in a dose-dependent manner.CONCLUSION: Our study suggests that ENMD-1068 is effective in suppressing the growth of endometriosis, which might be attributed to the drug's antiangiogenic and antiinflammatory activities.