State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.
Eye Institute of Xiamen University, Xiamen, China.
Invest Ophthalmol Vis Sci. 2019 Sep 3;60(12):3776-3785. doi: 10.1167/iovs.19-26928.
To investigate the therapeutic effects of targeting signal transducer and activator of transcription-3 (STAT3) activation on the ocular surface damage of dry eye in mice.
Adult Balb/C and C57BL/6 mice with benzalkonium chloride (BAC) treatment, lacrimal gland excision, and meibomian gland dysfunction were used as dry eye models. The levels of phosphorylated STAT3 (p-STAT3) were detected with immunofluorescence staining and Western blotting. STAT3 inhibition was performed by topical application of STAT3 inhibitor S3I-201. Corneal epithelial barrier function, tear production, and conjunctival goblet cell density were quantified with fluorescein sodium staining, phenol red cotton test, and histochemical staining. The expressions of matrix metalloproteinase (MMP)-3/9, TUNEL, and inflammation cytokines were assessed with immunofluorescence staining, qPCR, and ELISA assays. The therapeutic effect of S3I-201 was further compared with the Janus kinase inhibitor tofacitinib and ruxolitinib.
Elevated levels of nuclear p-STAT3 were detected in the corneal and conjunctival epithelium of three dry eye models. Topical application of S3I-201 improved corneal epithelial barrier function, increased tear production and conjunctival goblet cell density in BAC-induced dry eye mice. Moreover, S3I-201 decreased the expression of MMP-3/9, suppressed the apoptosis of corneal and conjunctival epithelial cells, and reduced the levels of IL-1β, IL-6, IL-17A, and IFN-γ. Compared with tofacitinib and ruxolitinib, the STAT3 inhibitor S3I-201 showed superior improvement of tear production and inflammatory cytokine expression in lacrimal gland.
Elevated STAT3 activation is involved in the pathogenesis of dry eye, while targeting STAT3 effectively alleviates BAC-induced ocular surface damage.
研究靶向信号转导子和转录激活子 3（STAT3）激活对小鼠干燥性眼表损伤的治疗作用。
采用苯扎氯铵（BAC）处理、泪腺切除和睑板腺功能障碍的成年 Balb/C 和 C57BL/6 小鼠作为干眼症模型。通过免疫荧光染色和 Western blot 检测磷酸化 STAT3（p-STAT3）的水平。通过局部应用 STAT3 抑制剂 S3I-201 抑制 STAT3。通过荧光素钠染色、酚红棉试验和组织化学染色定量评估角膜上皮屏障功能、泪液生成和结膜杯状细胞密度。通过免疫荧光染色、qPCR 和 ELISA 测定评估基质金属蛋白酶（MMP）-3/9、TUNEL 和炎症细胞因子的表达。进一步比较 S3I-201 与 Janus 激酶抑制剂托法替尼和鲁索利替尼的治疗效果。
在三种干眼症模型的角膜和结膜上皮中均检测到核 p-STAT3 水平升高。S3I-201 局部应用可改善 BAC 诱导的干眼症小鼠的角膜上皮屏障功能，增加泪液生成和结膜杯状细胞密度。此外，S3I-201 降低了 MMP-3/9 的表达，抑制了角膜和结膜上皮细胞的凋亡，并降低了 IL-1β、IL-6、IL-17A 和 IFN-γ 的水平。与托法替尼和鲁索利替尼相比，STAT3 抑制剂 S3I-201 在改善泪液生成和炎症细胞因子表达方面表现出更好的效果。
升高的 STAT3 激活参与了干眼症的发病机制，而靶向 STAT3 可有效缓解 BAC 诱导的眼表损伤。
