Combination therapy with telmisartan and parecoxib induces regression of endometriotic lesions
Combination therapy with telmisartan and parecoxib induces regression of endometriotic lesions
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DOI：
10.1111/bph.13874
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发表时间：
2017-08-01
影响因子：
7.3
通讯作者：
Laschke, Matthias W.
中科院分区：
文献类型：
--
作者：
Nenicu, Anca;Gu, Yuan;Laschke, Matthias W.
背景和结论：替米沙坦可抑制增生性病变的发展。然而，该药物也上调了考克斯-2的表达，这被认为促进了子宫内膜异位症的进展。因此，在本研究中，我们分析了替米沙坦和考克斯-2抑制剂的联合治疗是否比单独应用替米沙坦更有效地治疗子宫内膜异位病变。实验方法在C57 BL/6小鼠的腹膜腔中诱导子宫内膜异位病变，每天腹膜内注射替米沙坦（10 mg.kg（-1））、帕瑞考昔（5 mg.kg（-1））、替米沙坦和帕瑞考昔的组合或载体。通过高分辨率超声成像以及免疫组织化学和蛋白质印迹分析，研究了4周以上对病变存活、生长、血管形成、神经支配和蛋白质表达的治疗效果。当与帕瑞昔布联合使用时，替米沙坦的这种抑制作用更加明显。联合治疗导致病变内微血管密度降低以及增殖Ki 67阳性细胞数量减少和凋亡裂解半胱天冬酶-3阳性基质细胞数量增加。与对照组相比，这与考克斯-2、MMP-9和p-Akt/Akt的较低表达有关。这两种药物的应用进一步抑制了神经纤维的向内生长到lesions.CONCLUSIONS和IMPLICATIONS与替米沙坦和考克斯-2抑制剂的联合治疗代表了一种新的，有效的治疗子宫内膜异位症的药理学策略。
BACKGROUND AND PURPOSETelmisartan suppresses the development of endometriotic lesions. However, the drug also up-regulates the expression of COX-2, which has been suggested to promote the progression of endometriosis. Accordingly, in the present study we analysed whether a combination therapy with telmisartan and a COX-2 inhibitor may be more effective in the treatment of endometriotic lesions than the application of telmisartan alone.EXPERIMENTAL APPROACHEndometriotic lesions were induced in the peritoneal cavity of C57BL/6 mice, which were treated daily with an i.p. injection of telmisartan (10 mg.kg(-1)), parecoxib (5 mg.kg(-1)), a combination of telmisartan and parecoxib or vehicle. Therapeutic effects on lesion survival, growth, vascularization, innervation and protein expression were studied over 4 weeks by high-resolution ultrasound imaging as well as immunohistochemical and Western blot analyses.KEY RESULTSTelmisartan-treated lesions exhibited a significantly reduced lesion volume when compared with vehicle-treated controls and parecoxib-treated lesions. This inhibitory effect of telmisartan was even more pronounced when it was used in combination with parecoxib. The combination therapy resulted in a reduced microvessel density as well as lower numbers of proliferating Ki67-positive cells and higher numbers of apoptotic cleaved caspase-3-positive stromal cells within the lesions. This was associated with a lower expression of COX-2, MMP-9 and p-Akt/Akt when compared with controls. The application of the two drugs further inhibited the ingrowth of nerve fibres into the lesions.CONCLUSIONS AND IMPLICATIONSCombination therapy with telmisartan and a COX-2 inhibitor represents a novel, effective pharmacological strategy for the treatment of endometriosis.