Endometriose experimental heteróloga: estudos com reconstituição leucocitária ou injúria peritoneal aguda, em camundongos imunodeficientes

Several previous studies have demonstrated specific alterations in immune cell function in women with endometriosis, including a decrease in natural killer (NK) cell cytotoxicity and an enhanced activation state of monocytes and peritoneal macrophages. Certainly, ectopic attachment of endometrial tissue is likely associated with an inflammatory response that may aid in the establishment and progression of this disease, as cytokines, released by activated leukocytes, can dramatically affect endometrial cell proliferation, differentiation, apoptosis, and angiogenesis. To address these issues, we have developed a new model system using Rag2γ(c) mice allowing for xenographic studies of much longer duration and for the introduction of elements of a human immune system, what cannot be conducted in nude mice. In our study, we have examined the impact of the presence and absence of human immune cells on the initial establishment and early growth of experimental endometriosis. Paralelly, since IL-1α can stimulate the MMP system and VEGF production in normal wound repair, acute peritoneal injury, such as oophorectomy, may affect the establishment of experimental endometriosis, we have also studied the effect of an inflammatory-like microenvironment of a recent surgical procedure in attachment location, neoangiogenesis and growth of human endometrial tissue in the heterologous model of experimental endometriosis in immunodeficient mice. Indeed, we have examined the potential role of pioglitazone (PIO), a thiazolidinedione with potent antiinflammatory and anti-angiogenic effects, to prevent or reduce adhesion formation related to post-surgical- induced experimental endometriosis. We found a statistically significant reduction in the severity of peritoneal disease in Rag2γ(c) mice which also received adoptive transfer of human immune cells compared with mice that did not receive immune cells. In respect of recent post-operatory studies, the inflammatory-like microenvironment of a recent surgical procedure affects the attachment location, neoangiogenesis and growth of human endometrial tissue in this model. Moreover, 50% of mice receiving human tissue and PIO therapy were completely free of adhesions. Remaining mice in the PIO group exhibited a reduction in the extent of adhesions. PIO treatment of both mice and human endometrial tissues exhibited a further reduction in adhesion development (75% adhesion free). Our studies indicate that human immune cells readily track into the ectopic lesions established in mice, suggesting that a robust immune system is protective against the development of endometriosis. Indeed, surgical injury within the peritoneal cavity can significantly enhance the early invasion and vascularization of human tissues in an experimental chimeric model of endometriosis. Targeting inflammation with PIO may be an effective therapeutic approach to reduce post-surgical adhesions related to endometriosis.