Sjogren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090
Sjogren's syndrome associated dry eye in a mouse model is ameliorated by topical application of integrin α4 antagonist GW559090
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DOI：
10.1016/j.exer.2015.10.008
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发表时间：
2016-02-01
影响因子：
3.4
通讯作者：
Masli, Sharmila
中科院分区：
文献类型：
--
作者：
Contreras-Ruiz, Laura;Mir, Fayaz A.;Masli, Sharmila
干燥综合征是一种与外分泌腺炎症相关的自身免疫性疾病，临床表现为干眼症和口干。这种疾病中的干眼症涉及眼表组织角膜和结膜的炎症。虽然粘附分子的全身阻断已被用于治疗自身免疫性疾病，本研究的目的是确定局部应用整合素α 4粘附分子拮抗剂在与干燥综合征相关的干眼症小鼠模型中的治疗功效。为了评估这种自发发展的与干燥综合征相关的眼表面炎症，在TSP-1缺失小鼠（12周）中进行了评价。用含有0.1%地塞米松或30 mg/ml GW 559090或载体对照的局部制剂处理小鼠。评估角膜荧光素染色和结膜杯状细胞密度。进行实时PCR分析以评估角膜中炎症标志物IL-1 β和引流淋巴结中Tbet和ROR γ t的表达。在TSP-1缺失小鼠（>= 12周龄）中可检测到眼表面炎症，这导致角膜荧光素染色增加，表明角膜屏障破坏和结膜杯状细胞密度降低。与WT对照组相比，这些变化伴随着IL-1 β的角膜表达增加以及引流淋巴结中Th 1（Tbet）和Th 17（ROR γ t）标志物平衡的改变。与媒介物处理相比，局部施用的地塞米松和GW 559090显著减少角膜荧光素染色（分别为p = 0.023和p < 0.001）。与媒介物处理组相比，粘附分子阻断后角膜屏障完整性的改善与促炎性IL-1 β的角膜表达显著降低一致（两种处理均为p < 0.05）。在用0.1%地塞米松和GW 559090处理的小鼠中也注意到杯状细胞密度的显著改善（两者均为p < 0.05）。我们的结论是，类似于局部地塞米松，局部给药的GW 559090成功地改善了角膜屏障的完整性和炎症，在一个既定的眼表疾病与干燥综合征。(C)2015爱思唯尔有限公司版权所有。
Sjogren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin alpha 4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjogren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjogren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1 beta in the cornea and Tbet and ROR gamma t in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1 null mice (>= 12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1 beta as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (ROR gamma t) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p < 0.001, respectively). This improved corneal barrier integrity upon adhesion molecule blockade was consistent with significantly reduced corneal expression of pro-inflammatory IL-1 beta compared to vehicle treated groups (p < 0.05 for both treatments). Significant improvement in goblet cell density was also noted in mice treated with 0.1% dexamethasone and GW559090 (p < 0.05 for both). We conclude that similar to topical dexamethasone, topically administered GW559090 successfully improved corneal barrier integrity and inflammation in an established ocular surface disease associated with Sjogren's syndrome. (C) 2015 Elsevier Ltd. All rights reserved.