Department of Obstetrics and Gynecology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Obstetrics and Gynecology, Guangzhou Panyu Central Hospital, Guangzhou, China.
Am J Obstet Gynecol. 2014 Jun;210(6):531.e1-8. doi: 10.1016/j.ajog.2014.01.040. Epub 2014 Feb 1.
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.
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 μL 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 enzyme-linked immunosorbent assays and evaluated for the activation of nuclear factor-κB 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.
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-κB (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.
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.
蛋白酶激活受体 2 在子宫内膜异位症的发病机制中发挥着重要作用。我们研究了蛋白酶激活受体 2 拮抗剂 ENMD-1068 对非侵入性荧光小鼠模型中子宫内膜异位症发展的影响。
在裸鼠中创建了表达红色荧光蛋白的人子宫内膜异位症异种移植模型。在子宫内膜异位症诱导后，每天向小鼠腹腔内注射 25mg/kg 或 50mg/kg 的 ENMD-1068 或 200μL 的载体对照 5 天。然后计数、测量和收集在小鼠中形成的子宫内膜异位病灶。通过酶联免疫吸附试验评估病灶中白细胞介素 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。通过免疫组织化学用 Ki-67 和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记法分别评估细胞增殖和细胞凋亡。
ENMD-1068 呈剂量依赖性抑制子宫内膜异位病灶的发展（P<0.05），而对治疗小鼠的各种器官无明显毒性。一致地，ENMD-1068 呈剂量依赖性抑制病灶中白细胞介素 6 和核因子-κB（P<0.05）和细胞增殖（P<0.05）的表达，并增加凋亡细胞的百分比（P<0.05）。ENMD-1068 降低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<0.05），但无剂量依赖性。
我们的研究表明，ENMD-1068 能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。
