Lipoxin A4 Prevents the Progression of De Novo and Established Endometriosis in a Mouse Model by Attenuating Prostaglandin E2 Production and Estrogen Signaling

Rajesh Kumar,Lerisa Govender,Ronan Russell,Dela Golshayan,Chiara Pellegrini,Ilaria Gori,Geraldine O Canny,Jean-Christophe Wyss,Anne-Catherine Clerc,Masaru Katoh

doi:10.1371/journal.pone.0089742

Abstract

Endometriosis, a leading cause of pelvic pain and infertility, is characterized by ectopic growth of endometrial-like tissue and affects approximately 176 million women worldwide. The pathophysiology involves inflammatory and angiogenic mediators as well as estrogen-mediated signaling and novel, improved therapeutics targeting these pathways are necessary. The aim of this study was to investigate mechanisms leading to the establishment and progression of endometriosis as well as the effect of local treatment with Lipoxin A4 (LXA4), an anti-inflammatory and pro-resolving lipid mediator that we have recently characterized as an estrogen receptor agonist. LXA4 treatment significantly reduced endometriotic lesion size and downregulated the pro-inflammatory cytokines IL-1β and IL-6, as well as the angiogenic factor VEGF. LXA4 also inhibited COX-2 expression in both endometriotic lesions and peritoneal fluid cells, resulting in attenuated peritoneal fluid Prostaglandin E2 (PGE2) levels. Besides its anti-inflammatory effects, LXA4 differentially regulated the expression and activity of the matrix remodeling enzyme matrix metalloproteinase (MMP)-9 as well as modulating transforming growth factor (TGF)-β isoform expression within endometriotic lesions and in peritoneal fluid cells. We also report for first time that LXA4 attenuated aromatase expression, estrogen signaling and estrogen-regulated genes implicated in cellular proliferation in a mouse model of disease. These effects were observed both when LXA4 was administered prior to disease induction and during established disease. Collectively, our findings highlight potential targets for the treatment of endometriosis and suggest a pleotropic effect of LXA4 on disease progression, by attenuating pro-inflammatory and angiogenic mediators, matrix remodeling enzymes, estrogen metabolism and signaling, as well as downstream proliferative pathways.

Highlights

Endometriosis is a gynecological disorder, defined as the presence of endometrial-like tissue outside the uterine cavity, primarily on the pelvic peritoneum, ovaries, pouch of Douglas and rectovaginal septum
Three weeks after surgery we examined the presence and growth of endometriotic lesions in the peritoneal cavity of sham-operated control mice, vehicle-treated mice with endometriosis (‘vehicletreated with endometriosis (Veh)’) and Lipoxin A4 (LXA4)-treated mice with endometriosis (‘LXA4’)
In the present study we examined the effect of LXA4 on the IL1b-COX-2-Prostaglandin E2 (PGE2)-vascular endothelial growth factor (VEGF) axis as well as on Estrogen receptor alpha (ERa) and E2-regulated genes implicated in an experimental endometriosis model

Summary

Introduction

Endometriosis is a gynecological disorder, defined as the presence of endometrial-like tissue outside the uterine cavity, primarily on the pelvic peritoneum, ovaries, pouch of Douglas and rectovaginal septum. Endometriosis affects approximately 10% of women of reproductive age and is associated with local inflammation, the main clinical features being chronic pelvic pain, pain during intercourse and infertility [1]. The pathophysiology of this estrogen-dependent disease is enigmatic, with a poor correlation between the observed severity of the disease and the reported symptoms [2,3]. The medical treatment of endometriosis includes progestagens, gonadotropin-releasing hormone agonists and oral contraceptives. There is an unmet need for new drugs which inhibit the progression of endometriosis and alleviate pain and infertility, without affecting ovulation

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