*Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA; and †Pfizer, Inc, Medicine Development Group, San Diego, CA.
Cornea. 2014 Feb;33(2):177-83. doi: 10.1097/ICO.0000000000000019.
To determine the effects of topical Janus kinase inhibition on ocular surface inflammation and immunity.
Ophthalmic 0.003% tofacitinib (CP-690,550) was administered topically to inhibit Janus kinase activation at the ocular surface. Male BALB/c mice 6 to 8 weeks of age were subjected to corneal thermocautery and randomized to receive tofacitinib, vehicle, or no treatment. Corneas were subsequently excised for fluorescence-activated cell sorting and quantitative real-time reverse transcription polymerase chain reaction. Female C57BL/6 mice 6 to 8 weeks of age were exposed to desiccating stress to induce experimental dry eye disease and randomized to receive tofacitinib, tofacitinib and vehicle, vehicle, or no treatment. Corneal fluorescein staining was performed to evaluate clinical disease severity. The corneas and conjunctivae were harvested for immunohistochemical staining and quantitative real-time reverse transcription polymerase chain reaction.
After corneal thermocautery, it was found that tofacitinib treatment decreased the corneal infiltration of CD45+, Gr-1+, and CD11b+ cells on days 1 and 3. Transcripts encoding interleukin (IL)-1β and IL-6 were significantly decreased by tofacitinib treatment at post-thermocautery day 3. In experimental dry eye disease, tofacitinib treatment twice per day significantly decreased corneal fluorescein staining on days 12 and 15. The corneal infiltration of CD11b+ cells was significantly decreased by tofacitinib treatment twice per day. Tofacitinib treatment twice per day significantly increased the corneal expression of IL-1RA, and significantly decreased the corneal expression of tumor necrosis factor and IL-23. Further, tofacitinib treatment twice per day significantly decreased the conjunctival expression of IL-17A and significantly increased the conjunctival expression of FoxP3.
Topical ophthalmic tofacitinib, a Janus kinase inhibitor, suppressed ocular surface inflammation and immunity in experimental corneal thermocautery and dry eye disease.
确定局部 Janus 激酶抑制对眼表炎症和免疫的影响。
眼部给予 0.003%他氟前列素（CP-690,550）以抑制眼表 Janus 激酶激活。6 至 8 周龄雄性 BALB/c 小鼠行角膜热烙术，并随机接受他氟前列素、载体或无治疗。随后切除角膜进行荧光激活细胞分选和实时定量逆转录聚合酶链反应。6 至 8 周龄雌性 C57BL/6 小鼠行干燥应激暴露以诱导实验性干眼疾病，并随机接受他氟前列素、他氟前列素和载体、载体或无治疗。行角膜荧光素染色评估临床疾病严重程度。采集角膜和结膜行免疫组织化学染色和实时定量逆转录聚合酶链反应。
行角膜热烙术后发现，他氟前列素治疗在第 1 天和第 3 天降低了角膜 CD45+、Gr-1+和 CD11b+细胞浸润。他氟前列素治疗在热烙术后第 3 天显著降低了编码白细胞介素（IL）-1β和 IL-6 的转录物。在实验性干眼疾病中，他氟前列素每日两次治疗显著降低了第 12 天和第 15 天的角膜荧光素染色。他氟前列素每日两次治疗显著降低了角膜 CD11b+细胞浸润。他氟前列素每日两次治疗显著增加了角膜 IL-1RA 的表达，并显著降低了角膜肿瘤坏死因子和 IL-23 的表达。此外，他氟前列素每日两次治疗显著降低了结膜 IL-17A 的表达，并显著增加了结膜 FoxP3 的表达。
局部眼用他氟前列素，一种 Janus 激酶抑制剂，抑制了实验性角膜热烙术和干眼疾病中的眼表炎症和免疫。
