Therepeutic Response of Macrophage-Recruiting Chemokiness in Endometiotic Cells

Yale University, New Haven CT

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Abstract

Endometriosis is defined as the growth of endometrial glands and stromal cells in an aberrant or heterotopic location primarily under the dominant influence of estradiol. This disease is a common gynecological Droblem manifested primarily by chronic pelvic pain and infertility in women of reproductive age. The pathogenesis of the disorder remains to be fully elucidated. Recent attention has been focused on the role of macrophages. Paradoxically, interactions between endometriotic tissue and macrophages lead to the survival of the implants rather than to their demise. Several chemokines involved in the chemotaxis of monocytes/macrophages, including CCL2, CCL4, CCL5, CCL11, CXCL1, CXCL5 and CXCL8, have been shown to be increased in endometriotic lesions and/or peritoneal fluid from women with endometriosis. Nevertheless, a search of the literature failed to reveal a complete expression profile of chemokines responsible for recruiting monocytes/macrophages in association with endometriosis. We attempt to fill this void by generating a comprehensive profile of monocyte/macrophage-recruiting chemokines in endometriotic tissues. We posit that these chemokines can be targeted to reduce the abnormal influx of monocytes and macrophages. Thus, various endometrial cell types will be isolated using laser capture microdissection followed by evaluation of the expression profile of monocyte/macrophage-recruiting chemokines using microarray anallysis with real time RT-PCR and immunohistochemistry validation. The chemokines in the peritoneal fluid of patients will also be examined by enzyme-linked immunosorbant assays. We will also evaluate the effects of various treatments on the chemokine expression profile of endometriotic cells. Finally, we will evlauate the effects of therapies that target monocyte/macrophage-recruiting chemokines on the devevolpment and progress of endometriosis in a nude mouse model. This work could lead to the development of effective therapies to combat endometriosis. A successful treatment of endometriosis will be beneficial to the amelioration of clinical symptoms, such as infertility and pelvic pain.