Changing prostaglandin E2 (PGE 2 ) signaling during lesional progression and exacerbation of endometriosis by inhibition of PGE 2 receptor EP2 and EP4

[摘要] Purpose We investigated the change, if any, in prostaglandin E2 (PGE 2 ) signaling in endometriotic lesions of different developmental stages in mouse. In addition, we evaluated the effect of treatment of mice with induced deep endometriosis (DE) with inhibitors of PGE 2 receptor subtypes EP2 and EP4 and metformin. Methods Three mouse experimentations were conducted. In Experiment 1, female Balb/C mice were induced with endometriosis or DE and were serially sacrificed after induction. Experiments 2 and 3 evaluated the effect of treatment with EP2 and EP4 inhibitors and metformin, respectively, in mice with induced DE. Immunohistochemistry analysis of COX-2, EP2, and EP4, along with the extent of lesional fibrosis, was evaluated. Results The immunostaining of COX-2, EP2, and EP4 turned from activation to a stall as lesions progressed. Treatment with EP2/EP4 inhibitors in DE mice exacerbated endometriosis-associated hyperalgesia and promoted fibrogenesis in lesions even though it suppressed the PGE 2 signaling dose-dependently. In contrast, treatment with metformin resulted in increased PGE 2 signaling, concomitant with improved hyperalgesia, and retarded lesional fibrogenesis. Conclusions The PGE 2 signaling diminishes as endometriotic lesions progress. Treatment with EP2/EP4 inhibitors in DE mice exacerbates endometriosis, but metformin appears to be promising seemingly through the induction of the PGE 2 signaling.

[学科分类] 工业工程学

[关键词] cyclooxygenase 2;E series prostanoid receptor;endometriosis;fibrosis;mouse