Crucial role of hypoxia inducible factor in embryo implantation

Abstract

Objective: Endometriosis is a gynecological condition of which the primary symptoms are infertility and pelvic pain. Especially for infertility women, a new therapy which possesses reproductive expectation is needed. Hence, it is essential to explore inflammatory substances which have strong impact on the disease. Bradykinin (BK) is one of the most algogenic substances, also known as an inflammatory mediator in various diseases. Therefore, BK attracts much attention as a therapeutic target. As a first step toward understanding a possible role of bradykinin in endometriosis, we investigated the presence and the regulation of BK receptors in human endometriotic tissues. Material and method: This study protocol was approved by the institutional review boards. The expression of BK receptor (type I and II) in human endometriotic lesions was investigated by immunohistochemistory. Endometriotic stromal cells (ESC) were cultured with IL-1 (10ng/ml), followed by quantitative-PCR for BK receptors. In some experiments, after priming with IL-1 for 24h, ESC were stimulated with BK (1 M) for 8h, followed by quantitative-PCR for IL-6, COX-2 and endothelin-1. Result: Immunohistochemisty showed that BK receptors were present in epithelial and stromal cells in endometriotic lesions. IL-1 induced 10-fold increase in BK receptors mRNA in ESC (p<0.01). IL-1 induced IL-6 and COX-2 significantly (p<0.01) but not endothelin-1 mRNA. On addition of BK, IL-6 and COX-2 mRNA expressions were further enhanced to the levels of approximately 2-fold compared to IL-1 only (p<0.01). Endothelin-1 was increased 2-fold in ESC treated with IL-1 and BK, compared with control. These increases of mRNA expressions by BK were completely abrogated by 1 M HOE-140, an antagonist of BK receptor (p<0.01). Conclusion: In endometriotic lesions, BK receptors were present and served as chemical mediator. We showed that a strategy for blockingBK receptorsmight be anew therapy for endometriosis from the point of suppressing inflammation and pelvic pain.