The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling
The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling
复制标题
青蒿素类似物 SM934 通过调节 TLR4/NF-kB/NLRP3 信号传导缓解啮齿动物模型中的干眼病
DOI：
10.1038/s41401-020-0484-5
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发表时间：
2020-08-03
影响因子：
8.2
通讯作者：
Zuo, Jian-ping
中科院分区：
文献类型：
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作者：
Yang, Fang-ming;Fan, Di;Zuo, Jian-ping
干眼症是一种多因素的泪液和眼表疾病，其特征在于干燥和刺激的表现。虽然发病机制尚未完全阐明，但公认炎症在DED的发展和恶化中具有突出作用。β-氨基青蒿醚马来酸酯（SM 934）是具有抗炎和免疫抑制活性的水溶性青蒿素衍生物。本研究通过建立氢溴酸东莨菪碱（SCOP）和苯扎氯铵（BAC）诱导的大鼠DED模型，探讨SM 934对DED的治疗作用。我们发现，在SCOP诱导和BAC诱导的DED模型中，局部应用SM 934（0.1%，0.5%）可显著增加泪液分泌，维持结膜杯状细胞数量，减少角膜损伤，并降低结膜中炎症介质（TNF-α，IL-6，IL-10或IL-1 β）的水平。此外，SM 934处理减少了表达TLR 4的巨噬细胞在结膜中的积累，并抑制了炎性体组分的表达，即，髓样分化因子88（MyD 88）、Nod样受体蛋白3（NLRP 3）、包含CARD（ASC）的骨化相关斑点样蛋白和裂解的半胱天冬酶1。在LPS处理的RAW 264.7细胞中，我们证明用SM 934（10 μ M）预处理阻碍了TLR 4和下游NF-κ B/NLRP 3信号蛋白的上调。总之，青蒿素类似物SM 934通过同时保留眼表结构完整性和预防角膜和结膜炎症而对DED发挥治疗益处，提示SM 934在眼科治疗中的进一步应用，特别是对于DED。
Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by manifestations of dryness and irritation. Although the pathogenesis is not fully illuminated, it is recognized that inflammation has a prominent role in the development and deterioration of DED. beta-aminoarteether maleate (SM934) is a water-soluble artemisinin derivative with anti-inflammatory and immunosuppressive activities. In this study, we established scopolamine hydrobromide (SCOP)-induced rodent model as well as benzalkonium chloride (BAC)-induced rat model to investigate the therapeutic potential of SM934 for DED. We showed that topical application of SM934 (0.1%, 0.5%) significantly increased tear secretion, maintained the number of conjunctival goblet cells, reduced corneal damage, and decreased the levels of inflammatory mediators (TNF-alpha, IL-6, IL-10, or IL-1 beta) in conjunctiva in SCOP-induced and BAC-induced DED models. Moreover, SM934 treatment reduced the accumulation of TLR4-expressing macrophages in conjunctiva, and suppressed the expression of inflammasome components, i.e., myeloid differentiation factor88 (MyD88), Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and cleaved caspase 1. In LPS-treated RAW 264.7 cells, we demonstrated that pretreatment with SM934 (10 mu M) impeded the upregulation of TLR4 and downstream NF-kappa B/NLRP3 signaling proteins. Collectively, artemisinin analog SM934 exerts therapeutic benefits on DED by simultaneously reserving the structural integrity of ocular surface and preventing the corneal and conjunctival inflammation, suggested a further application of SM934 in ophthalmic therapy, especially for DED.