Proinflammatory cytokines in the pathogenesis of endometriosis and cervical insufficiency

Inflammation is a common characteristic of many pathological conditions, but it can play different roles depending on the source and pathways involved. By measuring cytokines, the signaling molecules of the immune system, we aimed to identify and evaluate the relative contribution of certain pathways in the development of two reproductive disorders: endometriosis and cervical insufficiency. In endometriosis, the pathways leading to the growth of endometrium outside the uterine cavity have not been elucidated, and whether inflammation is a result or trigger of endometriotic lesion growth is not known. In Chapter 2, we showed that 18 out of 26 cytokines were higher in the plasma of women with endometriosis compared to normal women. Also, surgical removal of endometriotic lesions altered circulating cytokine levels, indicating that lesions actively contribute to inflammation in endometriosis. In Chapter 3, we targeted inflammation in endometriosis using flavocoxid, an inhibitor of the eicosanoid pathway, and beta-caryophyllene, a cannabinoid 2 receptor agonist. Our experiments in human cell lines and a mouse model of endometriosis revealed a complex role of inflammation in endometriotic lesion growth and a potential interplay between the eicosanoid and cannabinoid pathways. In Chapter 4, we applied our knowledge of cytokine signaling to evaluate the role inflammation in cervical insufficiency, a pregnancy complication that can lead to recurrent midtrimester pregnancy losses and preterm birth. We showed that women with cervical insufficiency have higher levels of inflammatory cytokines than normal women, but only in cervicovaginal fluid, not in serum. Furthermore, cervical cerclage placement decreased the expression of inflammatory cytokines in cervicovaginal fluid only, indicating that inflammation is locally driven and can be decreased by intervention. In summary, this thesis provided important insights about the role of inflammation in these two conditions and the specific pathways that are involved and could be targeted for research and therapeutic purposes.