前列腺素E2激活视网膜微血管内皮细胞NLRP3炎症小体促进糖尿病视网膜病变的机制研究

Diabetic retinopathy (DR) is a common complication in patients with diabetes and has become an important cause of blindness. It was reported that the activation of inflammasome is related to the progress of DR, but the mechanism is unknown. Latest research reports that abnormally high level of PGE2 was detected in vitreous fluid of DR patients and PGE2 can activate NLRP3 inflammasomes. Our previous study found that human retinal microvascular endothelial cell (HRMEC) expresses 4 types of EP receptor; PGE2 treatment can upregulate NLRP3 expression in HRMECs; inflammatory effector of IL-1beta can induce RMECs injury; we also found in cancer research that PGE2/EPR signaling pathway activates a varieties of transcription factors associated with inflammation. Accordingly, we hypothesized that PGE2/EPR signaling pathway regulates the activity of NLRP3 inflammasomes involved in the pathological cause of exudative and proliferativ lesions of DR. This research program will use DR model to study the mechanism of PGE2 induced RMECs dysfunction by activating NLRP3 inflammasome and resulting in leakage and hyperplasia of vascular in diabetic retinopathy. The results of the reseach will help to find some targets of inhibiting DR occurrence and development in PGE2 signaling pathway and to save the vision of patients.

糖尿病视网膜病变（DR）是糖尿病患者常见并发症和致盲原因。有报导炎症小体的激活与DR密切相关但机制不明。新近报导DR患者玻璃体液中前列腺素E2（PGE2）水平异常升高；且PGE2与NLRP3炎症小体的激活有关。我们课题组前期研究发现，人视网膜微血管内皮细胞（HRMECs）表达4种PGE2受体（EPR），PGE2处理可上调HRMECs内NLRP3表达；炎症小体效应分子IL-1β促进RMECs损伤；在肿瘤研究中还发现PGE2/EPR信号通路的激活可上调多种与炎症相关的转录因子。据此，我们推测PGE2/EPR信号通路上调NLRP3炎症小体活性参与了DR微血管病变过程。本课题意在研究PGE2通过激活RMVECs内NLRP3炎症小体引起血管渗漏和增生，参与DR发生发展的机制，为针对PGE2信号通路及靶点研究干预措施，抑制DR血管病变的发生与发展，挽救DR患者的视力奠定科学基础。

糖尿病视网膜病变（DR）是糖尿病患者常见并发症和致盲原因。有报导炎症小体的激活与DR密切相关但机制不明。新近报导DR患者玻璃体液中前列腺素E2（PGE2）水平异常升高；且PGE2与NLRP3炎症小体的激活有关。在链脲佐菌素（STZ）诱导的糖尿病大鼠模型中，大鼠接受玻璃体腔注射PGE2，布他前列素（PGE2）/EP2R激动剂）或AH6809（EP2R拮抗剂）。视网膜组织学，光学相干断层扫描，视网膜的超微结构评估血管和生化指标。结果玻璃体腔注射PGE2和布他前列素可显著加速视网膜血管渗漏、白细胞粘附和内皮细胞损伤。AH6809预处理可以抑制STZ诱导的糖尿病大鼠细胞凋亡。此外，AH6809预处理人视网膜微血管内皮细胞可减弱PGE2-和布他前列素诱导的caspase 1活化，NLRP3与ASC的结合，以及EP2R偶联的cAMP/蛋白激酶A/cAMP反应元件结合蛋白的激活信号通路。PGE2/EP2R信号通路参与了STZ诱导的糖尿病视网膜病变的发生发展，可能作为糖尿病视网膜病变预防和治疗的潜在目标。