Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Laboratory of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Sci Rep. 2020 Oct 14;10(1):17268. doi: 10.1038/s41598-020-74159-w.
Dry eye syndrome (DES), a multifactorial disorder which leads to ocular discomfort, visual disturbance and tear film instability, has a rising prevalence and limited treatment options. In this study, a newly developed trypsin-like serine protease inhibitor (UAMC-00050) in a tear drop formulation was evaluated to treat ocular inflammation. A surgical animal model of dry eye was employed to investigate the potential of UAMC-00050 on dry eye pathology. Animals treated with UAMC-00050 displayed a significant reduction in ocular surface damage after evaluation with sodium fluorescein, compared to untreated, vehicle treated and cyclosporine-treated animals. The concentrations of IL-1α and TNF-α were also significantly reduced in tear fluid from UAMC-00050-treated rats. Additionally, inflammatory cell infiltration in the palpebral conjunctiva (CD3 and CD45), was substantially reduced. An accumulation of pro-MMP-9 and a decrease in active MMP-9 were found in tear fluid from animals treated with UAMC-00050, suggesting that trypsin-like serine proteases play a role in activating MMP-9 in ocular inflammation in this animal model. Comparative qRT-PCR analyses on ocular tissue indicated the upregulation of tryptase, urokinase plasminogen activator receptor (uPAR) and protease-activated receptor 2 (PAR2). The developed UAMC-00050 formulation was stable up to 6 months at room temperature in the absence of light, non-irritating and sterile with compatible pH and osmolarity. These results provide a proof-of-concept for the in vivo modifying potential of UAMC-00050 on dry eye pathology and suggest a central role of trypsin-like serine proteases and PAR2 in dry eye derived ocular inflammation.
干眼症（DES）是一种多因素疾病，可导致眼部不适、视觉障碍和泪膜不稳定，其患病率不断上升，治疗选择有限。在这项研究中，评估了一种新开发的泪滴制剂中的胰蛋白酶样丝氨酸蛋白酶抑制剂（UAMC-00050），以治疗眼部炎症。使用干眼症手术动物模型研究 UAMC-00050 对干眼症病理的潜在作用。与未治疗、载体治疗和环孢素治疗的动物相比，用 UAMC-00050 治疗的动物在评估用荧光素钠后，眼表面损伤明显减少。来自 UAMC-00050 治疗大鼠的泪液中 IL-1α 和 TNF-α 的浓度也显著降低。此外，眼睑结膜（CD3 和 CD45）中的炎症细胞浸润也大大减少。在用 UAMC-00050 治疗的动物的泪液中发现了 pro-MMP-9 的积累和活性 MMP-9 的减少，这表明在该动物模型中，胰蛋白酶样丝氨酸蛋白酶在激活 MMP-9 引起的眼部炎症中起作用。对眼部组织的比较 qRT-PCR 分析表明，胰蛋白酶、尿激酶纤溶酶原激活物受体（uPAR）和蛋白酶激活受体 2（PAR2）上调。在没有光照的情况下，UAMC-00050 制剂在室温下可稳定长达 6 个月，无刺激性且无菌，具有相容的 pH 值和渗透压。这些结果为 UAMC-00050 对干眼症病理的体内修饰潜力提供了概念验证，并表明胰蛋白酶样丝氨酸蛋白酶和 PAR2 在干眼症引起的眼部炎症中起核心作用。
