O-99:Inflammatory Mediators OfEndometriosis Pathogenesis



Endometriosis affects about 70 million women world-wide and accounts for 1-2 billion US dollars in medical and surgical health expenses annually. A variety of theories has been promulgated regarding the etiology of endometriosis, yet the precise pathogenic mechanisms responsible for its associated pelvic pain and infertility remain unknown. The establishment of endometriosis lesions in extrauterine locations (eg, peritoneum, ovary or rectovaginal septum) requires the invasion and neovascularization of endometrial stromal and gland cells within the extracellular matrix of the ectopic foci. Recruitment of innate immune cells into endometriotic lesions and the peritoneal cavity is a key pathophysiological feature of the syndrome. Neutrophils and macrophages are attracted from the circulation via chemokines, including ENA-78, eotaxin, IL-8, MCP-1 and RANTES. This presentation will focus on the latter, a C-C or beta-chemokine with chemoattractant properties for monocytes, T cells and eosinophils that has been extensively characterized in our laboratory. Concentrations of RANTES are elevated in the peritoneal fluid of women with endometriosis and correlate with disease stage. Stromal cells in ectopic implants appear to be the primary cellular source of RANTES. Analyses of the human RANTES gene promoter in endometrial and endometriotic cells indicate that proinflammatory cytokines (eg, IL-1-beta and TNF-alpha) regulate RANTES expression via the activation of the transcription factor NF-kappaB. Estrogens and dioxins can increase RANTES production and appear to exacerbate endometriosis. Agents that inhibit NF-kappaB signaling reduce RANTES mRNA and protein production. Two general classes include certain nonsteroidal anti-inflammatory drugs (NSAIDs) and thiazolidinediones (TZDs). These pharmaceuticals have been tested using in vitro cultures of human endometriosis cells and also in mouse and baboon models of endometriosis. These compounds show promise in the reduction of lesion volume. The findings of these preclinical studies promise that new opportunities for drug discovery exist and that refinement of treatment choices for endometriosis will emerge.