前列腺素F2α调控干燥综合征泪腺纤维化的机制研究

Sjogren syndrome dry eye is a difficult point in clinical treatment, and its pathogenesis is unclear, previous studies have suggested that it is caused by lymphocyte infiltration of lacrimal gland tissue. In addition to inflammatory cell infiltration, lacrimal gland fibrosis is also an important pathological feature of Sjogren syndrome. Lacrimal gland fibrosis may play an important role in the pathogenesis of Sjogren syndrome dry eye and be also an important cause of its clinical refractory. Prostaglandin F2α (PGF2α) is an inflammatory mediator that promotes fibrosis. Our previous study found that PGF2α analog can cause dry eye-like ocular surface damage and increase the expression of extracellular matrix genes in lacrimal gland tissue. The role and mechanism of lacrimal gland fibrosis caused by PGF2α in Sjogren syndrome has not been reported. PGF2α has previously been shown to induce tissue fibrosis via its FP receptor-activated TGF-β-Smads and/or TGF-β-Smads-independent Rho-ROCK signaling pathway. In order to propose new ideas for the treatment of Sjogren syndrome dry eye in the future, this project will reveal the pathogenesis and therapeutic targets of lacrimal gland fibrosis in Sjogren syndrome using clinical samples, Sjogren syndrome and FP receptor knockout mice, primary cultured lacrimal gland fibroblasts, PGF2α analog and inhibitors of FP receptor and TGF-β-Smads and/or Rho-ROCK signaling pathways.

干燥综合征引起严重干眼的发病机制不清，是临床治疗难点，以往研究认为其可能由淋巴细胞浸润泪腺组织引起。除炎症细胞浸润外，泪腺组织纤维化也是干燥综合征重要的病理特征。泪腺纤维化可能在干燥综合征干眼发病机制中起重要作用，并可能是其难治的原因。我们前期研究发现可促进纤维化的炎症介质前列腺素F2α（PGF2α），其衍生物点眼后引起小鼠干眼样眼表损伤和泪腺组织细胞外基质基因表达增多。PGF2α在干燥综合征泪腺纤维化的作用及机制尚无研究报道。以往已证明PGF2α可通过其FP受体激活TGF-β-Smads和/或不依赖TGF-β-Smads的Rho-ROCK信号通路诱导组织纤维化。本项目拟通过临床样本、干燥综合征和FP受体基因敲除的小鼠及原代培养的泪腺成纤维细胞，并用PGF2α衍生物、FP受体及相关信号通路的抑制剂进行研究，以揭示干燥综合征泪腺纤维化的机制及治疗靶点，为今后干燥综合征干眼的治疗提供新的思路。

干燥综合征引起严重干眼的发病机制不清，是临床治疗的难点。本项目应用临床标本和东莨菪碱联合干燥环境诱导的干燥综合征模型小鼠观察干燥综合征干眼严重程度和泪腺组织纤维化及PGF2α水平的相关性；并应用干燥综合征模型小鼠和原代培养的泪腺成纤维细胞，探讨PGF2α诱导泪腺成纤维细胞合成细胞外基质的作用及其激活的信号通路；最后通过FP受体抑制剂处理干燥综合征模型小鼠，评估FP受体的抑制对干燥综合征泪腺纤维化改善及其干眼的治疗作用。我们的研究结果显示，干燥综合征干眼严重程度与泪腺纤维化及泪腺组织中PGF2α的表达水平具有显著相关，同时揭示了PGF2α通过FP受体激活泪腺成纤维细胞 (LGFs）Rho-ROCK信号通路，PGF2α刺激泪腺成纤维细胞分泌TGFβ1并激活TGFβ1/Smads信号通路，Rho-ROCK和TGFβ1/Smads信号通路协同作用，促进细胞外基质合成，诱导泪腺组织纤维化，促进干眼的发生；我们进一步明确了FP受体的抑制可改善干燥综合征小鼠泪腺纤维化和治疗其干眼。本项目成功揭示干燥综合征泪腺纤维化的机制及治疗靶点，为今后干燥综合征干眼的治疗提供新的思路。