血小板在子宫内膜异位症发生发展中的作用研究

Endometriosis is a common gynecologic disorder in women of reproductive age. Its symptoms include dysmenorrhea, chronic pelvic pain, and infertility, impacting negatively on women’s life quality and productivity and exerting a heavy economic burden on the society. Its prevalence is reportedly increased in recent years, yet its pathogenesis is still poorly understood. As a result, its clinical management is still challenging. Although surgery and anti-estrogen therapy may reduce pain and relieve other associated symptoms, however, the relief is often short-term and the recurrence risk is high. Wound healing is a highly dynamic and complicated process, in which platelets play a critical role in hemostasis, immune responses, and tissue remodeling. While the ectopic endometrium undergoes cyclic bleeding and tissue repair process along with the patient’s menstrual cycle, the platelets would be activated and aggregated in and around lesions, therefore we propose that the endometriotic lesion effectively becomes a wound that repeatedly injured and healed. Our previous study showed that activated platelets promoted endometrial stromal cells proliferation, and anti-platelets therapy significantly reduced the lesion size in the mouse model. Our study is to further investigate the role of platelets in the development and progression of endometriosis, and search for new therapy to relieve symptoms, promote fertility and life quality.

子宫内膜异位症（EMs）症状主要为痛经及不孕，目前手术或药物治疗效果不佳且易复发，严重影响妇女生育功能及生活质量。其发病机制目前仍不明确，存在多种学说，并提出它是一种免疫炎性、雌激素及血管生成依赖性疾病。出血是组织损伤的标志，而内异症是一个出血性疾病。由于异位内膜随月经周期发生周期性出血，因此提出内异症病灶可能是一个反复损伤愈合的伤口。活化血小板可能正是借助了伤口愈合的固有机制，释放大量细胞因子及各种生长因子，募集炎症细胞，促进炎症反应，增强血管新生，促进组织纤维化，从而促进疾病发展。前期实验已经证实活化血小板可促进异位内膜间质细胞增殖；抗血小板治疗对缩小模型小鼠病灶有效。因此，血小板可能在内异症发生发展过程中起重要作用，本课题旨在阐明血小板在内异症发生发展中的作用机制并研究从血小板作用的角度进行临床干预治疗的可能途径，为寻求新的治疗方法提供理论依据，改善患者症状，提高生育能力及生活质量。

目前尚无有效治疗内异症的非激素药物，对内异症的发生发展的机理尚不明确。本课题从血小板作用的角度对内异症进行研究，探究血小板促进子宫内膜异位症发展的作用及相关分子机制，对内异症的发生发展机理有一个飞跃的认识，并对其干预靶点及无创诊断也有全新的认识。本课题组创新性的提出子宫内膜异位症病灶是一个反复损伤修复的伤口的假说，并研究证实内异症患者异位内膜病灶中存在血小板活化聚集，活化血小板正是借助了伤口愈合的固有机制与复杂过程，释放大量趋化因子、细胞因子及各种生长因子，在参与内异症发展过程中免疫炎性反应、血管生成及病灶纤维化都起到至关重要的作用。同时，血小板与内异症病灶及局部腹腔内环境相互作用，共同促进内异症病灶生长，疾病发展；此外本研究通过建立小鼠内异症模型, 并通过制备可溶性重组P-选择素蛋白，对内异症模型小鼠进行可溶性P-选择素蛋白治疗，证实可溶性P-选择素蛋白对缩小模型小鼠病灶、缓解痛觉过敏有效，确定血小板以及P-选择素在内异症发生、发展中的作用，可溶性P选择素蛋白体内治疗内异症完成成果转化，申请发明专利一项，其治疗内异症安全有效，完全有望成为新的安全的内异症治疗方法；最后本课题还探究了新的内异症无创诊断的生物学标志物，证实外周血存在某种高凝状态，且外周血血小板活化率及相关凝血指标均高于正常对照妇女。