Department of Obstetrics and Gynecology, University of Toyama, Japan.
Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan.
Eur J Pain. 2018 Mar;22(3):501-510. doi: 10.1002/ejp.1133. Epub 2017 Oct 16.
Endometriosis is a gynaecological disease exhibiting severe pelvic pain, but the mechanism of pain production remains unknown. Bradykinin (BK) is known as an inflammatory mediator, and shows elevated levels in inflammatory diseases such as rheumatoid arthritis. In the present study, we evaluated whether BK is involved in endometriosis-related pain.
Endometriotic lesions were used for immunohistochemistry. Primary cultures of endometriotic stromal cells (ESC) were stimulated with IL-1β and/or BK. Quantitative RT-PCR was used to evaluate the mRNA expressions of BK receptors (BKR) and endothelin-1 in ESC. The concentration of endothelin-1 in cystic fluid of endometrioma or non-endometrioma was measured with ELISA. The conditioned medium of ESC stimulated with IL-1β and/or BK was injected intraplantarly in mice, and evaluated whether pain-related licking behaviour was elicited.
The expressions of BK and BKR in endometriotic lesions were observed by immunohistochemistry. In vitro experiments showed that IL-1β induced BKR-B1 and B2 on ESC. Activation of these receptors by BK significantly induced endothelin-1 expression in ESC, which was negated completely by HOE-140, a BKR-B2 antagonist. The cystic fluid of endometrioma contained higher amount of endothelin-1 compared to non-endometrioma. Intraplantar injection of the conditioned medium of ESC treated with IL-1β and BK significantly induced licking behaviour, which was suppressed with BQ-123, an endothelin type-A receptor antagonist.
The present study demonstrated the presence and the function of the BK axis in endometriosis, and established a potential new therapy target for endometriosis-related pain.
The present study demonstrated (1) the presence and the function of the BK system in endometriosis, (2) activation of BKR induced endothelin-1 in endometriotic lesion and (3) blocking endothelin-1 was effective to decrease pain.
子宫内膜异位症是一种妇科疾病，表现为严重的盆腔疼痛，但疼痛产生的机制尚不清楚。缓激肽（BK）是一种炎症介质，在类风湿关节炎等炎症性疾病中表达升高。在本研究中，我们评估了 BK 是否参与了与子宫内膜异位症相关的疼痛。
使用免疫组织化学法检测子宫内膜异位症病灶。用 IL-1β和/或 BK 刺激子宫内膜间质细胞（ESC）的原代培养物。用定量 RT-PCR 评估 ESC 中 BK 受体（BKR）和内皮素-1 的 mRNA 表达。用 ELISA 测量卵巢子宫内膜异位囊肿或非子宫内膜异位囊肿囊液中的内皮素-1 浓度。将 ESC 用 IL-1β和/或 BK 刺激后的条件培养基注入小鼠足底，评估是否引起与疼痛相关的舔舐行为。
免疫组织化学法观察到子宫内膜异位症病灶中 BK 和 BKR 的表达。体外实验表明，IL-1β诱导 ESC 上的 BKR-B1 和 B2。BK 激活这些受体显著诱导 ESC 中内皮素-1 的表达，而 BKR-B2 拮抗剂 HOE-140 则完全阻断了这一作用。与非子宫内膜异位囊肿相比，子宫内膜异位囊肿囊液中内皮素-1 的含量更高。ESC 用 IL-1β和 BK 处理后的条件培养基足底注射显著诱导舔舐行为，而内皮素 A 型受体拮抗剂 BQ-123 则抑制了这种行为。
本研究证明了 BK 轴在子宫内膜异位症中的存在和功能，并为子宫内膜异位症相关疼痛建立了一个潜在的新治疗靶点。
本研究证明了（1）BK 系统在子宫内膜异位症中的存在和功能，（2）BKR 的激活诱导了子宫内膜异位症病灶中的内皮素-1，（3）阻断内皮素-1 可有效减轻疼痛。
