title: Lipoxin A₄ prevents the progression of de novo and established endometriosis in a mouse model by attenuating prostaglandin E₂ production and estrogen signaling.
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.
authors.affiliation: Mucosal Immunity Laboratory, Department of Gynecology, Obstetrics and Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland ; Transplantation Centre and Transplantation Immunopathology Laboratory, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Mucosal Immunity Laboratory, Department of Gynecology, Obstetrics and Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Clerc
authors.affiliation: Mucosal Immunity Laboratory, Department of Gynecology, Obstetrics and Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Gori
authors.affiliation: Mucosal Immunity Laboratory, Department of Gynecology, Obstetrics and Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Ronan
authors.initials: R
authors.lastname: Russell
authors.affiliation: Mucosal Immunity Laboratory, Department of Gynecology, Obstetrics and Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pellegrini
authors.affiliation: Transplantation Centre and Transplantation Immunopathology Laboratory, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Lerisa
authors.initials: L
authors.lastname: Govender
authors.affiliation: Transplantation Centre and Transplantation Immunopathology Laboratory, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Wyss
authors.affiliation: Transplantation Centre and Transplantation Immunopathology Laboratory, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Dela
authors.initials: D
authors.lastname: Golshayan
authors.affiliation: Mucosal Immunity Laboratory, Department of Gynecology, Obstetrics and Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
authors.forename: Geraldine O
authors.initials: GO
authors.lastname: Canny
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D053898:Biosynthetic Pathways / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D015232:Dinoprostone / Q000096:biosynthesis*; D004715:Endometriosis / Q000503:physiopathology / Q000517:prevention & control*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D044045:Lipoxins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D017931:DNA Primers; D004967:Estrogens; D053583:Interleukin-1beta; D015850:Interleukin-6; D044045:Lipoxins; D042461:Vascular Endothelial Growth Factor A; C040527:lipoxin A4; D001141:Aromatase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone