Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
Department of Ophthalmology, Mackay Memorial Hospital, Taipei, Taiwan.
Cornea. 2024 Mar 1;43(3):378-386. doi: 10.1097/ICO.0000000000003427. Epub 2023 Nov 27.
The purpose of this study was to extensively evaluate the efficacy of integrin αvβ3 antagonists for the treatment of experimental dry eye (EDE).
Vitronectin, an αvβ3 ligand, was used to induce tumor necrosis factor-α gene expression in human THP-1 macrophages. To induce EDE, C57BL/6 mice were housed in a low-humidity controlled environment chamber and injected subcutaneously with scopolamine for 7 days. Subsequently, αvβ3 antagonists, including RGDfD, c(RGDfD), c(RGDiD), c(RGDfK), ATN-161, SB273005, and cilengitide, were administered topically to EDE animals under controlled environment chamber conditions. Corneal epithelial damage in EDE was assessed by fluorescein staining. The density of conjunctival goblet cells and secretion of tears was measured by period acid-Schiff staining and phenol red-impregnated cotton threads, respectively. Inflammation markers, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-17A, and metalloproteinase (MMP)-9, in the pooled cornea and conjunctiva tissues were examined by real-time polymerase chain reaction.
The inhibitory effects of αvβ3 antagonists on the vitronectin-induced tumor necrosis factor-α gene expression and integrin-mediated inflammatory signaling were validated in THP-1 macrophages. αvβ3 antagonists ameliorated the impairment of the corneal epithelial barrier with varying therapeutic efficacies, compared with vehicle-treated mice. c(RGDfD) and c(RGDiD) significantly protected against goblet cell loss, tear reduction, and proinflammatory gene expression in EDE.
Topical applications of αvβ3 antagonists yield therapeutic benefits in EDE by promoting corneal epithelial defect healing and reducing inflammation. Antagonistic targeting αvβ3 may be a novel promising strategy to treat patients with dry eye disease.
本研究旨在广泛评估整合素 αvβ3 拮抗剂治疗实验性干眼症（EDE）的疗效。
使用 vitronectin（一种 αvβ3 配体）诱导人 THP-1 巨噬细胞中肿瘤坏死因子-α 基因表达。为了诱导 EDE，将 C57BL/6 小鼠饲养在低湿度控制环境室中，并皮下注射东莨菪碱 7 天。随后，在控制环境室条件下，将 αvβ3 拮抗剂（包括 RGDfD、c（RGDfD）、c（RGDiD）、c（RGDfK）、ATN-161、SB273005 和 cilengitide）局部施用于 EDE 动物。通过荧光素染色评估 EDE 中的角膜上皮损伤。通过过碘酸-Schiff 染色测量结膜杯状细胞密度，通过酚红浸渍棉线测量泪液分泌。通过实时聚合酶链反应检测聚合角膜和结膜组织中的炎症标志物，包括肿瘤坏死因子-α、白细胞介素（IL）-1β、IL-6、IL-17A 和基质金属蛋白酶（MMP）-9。
在 THP-1 巨噬细胞中验证了 αvβ3 拮抗剂对 vitronectin 诱导的肿瘤坏死因子-α 基因表达和整合素介导的炎症信号的抑制作用。与载体处理的小鼠相比，αvβ3 拮抗剂在不同治疗效果下改善了角膜上皮屏障的损伤。c（RGDfD）和 c（RGDiD）可显著防止 EDE 中杯状细胞丢失、泪液减少和促炎基因表达。
αvβ3 拮抗剂通过促进角膜上皮缺损愈合和减少炎症在 EDE 中产生治疗益处。拮抗靶向 αvβ3 可能是治疗干眼症患者的一种新的有前途的策略。
