Lin Zhirong, Verma Bhupender, Zhu Shuyan, Zidan Asmaa A, Najafi Sheyda, Naderi Amirreza, Elbasiony Elsayed, Yin Jia
Schepens Eye Research Institute of Mass Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
Affiliated Xiamen Eye Center of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Invest Ophthalmol Vis Sci. 2025 Aug 1;66(11):58. doi: 10.1167/iovs.66.11.58.
Calcitonin gene-related peptide (CGRP) level is reduced in the tears of patients with dry eye disease (DED). The current study aims to investigate the expression and therapeutic potential of CGRP as topical eye drops in treating experimental DED.
Human corneal epithelial cells (CECs) were cultured under hyperosmotic stress (HS) and the effects of CGRP on cell viability, proliferation, migration, and apoptosis were determined in vitro. The expression of CGRP in the cornea and trigeminal ganglion (TG) of desiccating stress-induced experimental DED mice was determined. CGRP or albumin control were topically applied thrice daily for two weeks in DED mice and DED parameters were assessed clinically. Cornea and conjunctiva were collected separately after treatment, and cell proliferation and tissue inflammation were determined using immunostaining and flow cytometry.
Experimental DED mice showed significantly reduced CGRP mRNA and protein expression in their cornea and TG. CGRP promoted proliferation and downregulated apoptosis, TNF-α, IL-1β, and IL-6 mRNA levels during HS in cultured CECs. Clinically, topical application of CGRP significantly decreased corneal fluorescein staining score, increased tear break-up time, and preserved corneal epithelium in DED mice. In the cornea, CGRP significantly promoted epithelial proliferation and reduced infiltrating CD45+ leukocytes, and TNF-α and IL-1β expression in vivo. CGRP treatment did not significantly affect the frequency of CD45+ leukocytes in the conjunctiva.
Our data demonstrate that CGRP expression in the cornea and TG is downregulated in DED. Topical CGRP treatment ameliorates DED severity by promoting epithelial proliferation and suppressing inflammation in the cornea.
干眼症（DED）患者泪液中降钙素基因相关肽（CGRP）水平降低。本研究旨在探讨CGRP作为局部滴眼液在治疗实验性DED中的表达及治疗潜力。
在高渗应激（HS）条件下培养人角膜上皮细胞（CEC），并在体外测定CGRP对细胞活力、增殖、迁移和凋亡的影响。测定干燥应激诱导的实验性DED小鼠角膜和三叉神经节（TG）中CGRP的表达。对DED小鼠每日局部应用CGRP或白蛋白对照3次，持续2周，并临床评估DED参数。治疗后分别收集角膜和结膜，采用免疫染色和流式细胞术测定细胞增殖和组织炎症。
实验性DED小鼠角膜和TG中CGRP mRNA和蛋白表达显著降低。在HS条件下，CGRP促进培养的CEC增殖，下调凋亡、TNF-α、IL-1β和IL-6 mRNA水平。临床上，局部应用CGRP可显著降低DED小鼠角膜荧光素染色评分，增加泪膜破裂时间，并保留角膜上皮。在角膜中，CGRP在体内显著促进上皮增殖，减少浸润的CD45+白细胞以及TNF-α和IL-1β表达。CGRP治疗对结膜中CD45+白细胞频率无显著影响。
我们的数据表明，DED中角膜和TG中CGRP表达下调。局部应用CGRP治疗可通过促进上皮增殖和抑制角膜炎症来改善DED严重程度。
