The role of lipid mediators in the aetiology of endometriosis

Abstract

Endometriosis is one of the most common, chronic gynaecological disorders characterised by the histological presence of endometrial-like tissues outside the uterus. The most frequent location of ectopic endometrial lesions is the pelvic cavity causing chronic inflammation, fertility problems and a wide range of pain symptoms. Despite extensive research efforts, reliable diagnostic biomarkers still do not exist and the aetiology and underlying pathophysiology of the disease have not yet been completely elucidated. Eicosanoids and related hydroxy fatty acids are a rich class of biologically active oxygenated metabolites derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA). These lipid mediators are produced locally in cells through biosynthetic pathways of cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) enzyme pathways as well as in a non-enzymatic manner and regulate an array of physiological and pathological processes. Biological fluid specimens, such as plasma and peritoneal fluid, are a rich source of oxygenated lipid metabolites. So far, only a limited number of lipid mediators have been studied in endometriosis. The main aim of this study was to simultaneously measure 79 oxygenated lipid mediators in plasma and peritoneal fluid specimens obtained from consenting women with and without endometriosis using liquid chromatography coupled to electrospray ionisation tandem mass spectrometry (LC/ESI-MS/MS). Lipid mediator profiles in peritoneal specimens would offer insights into the local pathophysiological processes in the peritoneum and analysis of plasma samples would indicate their systemic effects. Lipid mediators did not show clear trends in plasma with regard to any biosynthetic pathway from women with endometriosis compared to those without. In contrast to plasma, although significant changes were not detected, the lipid mediator profiles in peritoneal fluid showed apparent alterations. Nearly all tested metabolites were present in decreased concentrations in the peritoneal fluid from women diagnosed with endometriosis. The most prominent reductions were observed for 15-LOX derived metabolites. Since 15-LOX metabolites are endogenous ligands for peroxisome proliferator-activated receptor gamma (PPARG) it was hypothesised that the low concentration of PPARG ligands could lead to the disturbed regulation of PPARG mediated pathways, such as downregulating scavenger receptor CD36 expression in peritoneal macrophages from women with endometriosis. To extend our knowledge about the role of PPARG in the pathomechanism of endometriosis, expression of 15-LOX, PPARG and CD36 was investigated in ectopic lesions, eutopic endometrium, peritoneal cells and peritoneal wall samples from women with endometriosis and in eutopic endometrium and peritoneal cells from women without endometriosis using qRT-PCR and immunohistochemistry methods. In conclusion, data presented in this thesis did not support the theory that PPARG mediated processes were disturbed in endometriosis. However, results highlight the role of PPARG in reducing the rate of proliferation and steroidogenesis of ectopic lesions. In addition this research also points out that there are complex, multilevel relationships within the peritoneal environment. A better understanding of these interactions is necessary to elucidate the aetiology and pathomechanisms of endometriosis to improve management of this unmet clinical need.

Date of Award	31 Dec 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Kay Marshall (Supervisor) & Anna Nicolaou (Supervisor)