Nintedanib Eye Drops Inhibit Alkali Burn-Induced Corneal Neovascularization Via RAP1/MEK/ERK Signaling Pathway.

Abstract

PURPOSE: To investigate the effect of topical nintedanib (NTD) eye drops on alkali burn-induced corneal neovascularization (CNV) and the mechanisms involved. METHODS: The effects of NTD on the proliferation, migration, and tube-like structure formation assays were evaluated in human umbilical vein endothelial cells (HUVECs). RNA sequencing was performed to identify differentially expressed genes following NTD treatment. The expression of the RAP1A/MEK/HIF-1α axis was assessed by immunofluorescence (IF) and western blotting in HUVECs after NTD treatment. A CNV mouse model was established, and topically administered NTD eye drops three times daily for 10 consecutive days. Hematoxylin and eosin staining and IF were performed on days 3 and 7 after modeling. CNV was quantitatively analyzed after cardiac perfusion on day 10. RESULTS: In vitro, NTD inhibited the proliferation, migration, and tube-like structure formation of HUVECs. RAP1 and MAPK signaling pathways were enriched by RNA sequencing analysis. NTD downregulated the expressions of RAP1A, p-MEK, p-ERK1/2, HIF-1α, VEGFA, and VEGFR2 in VEGF-stimulated HUVECs. In vivo, NTD eye drops demonstrated appropriate osmolarity and pH values. Compared to the control and vehicle groups, NTD eye drops suppressed CNV, inflammation, and the expression of LYVE1, CD31, VEGFA, and RAP1 in the cornea. CONCLUSIONS: Topical NTD administration effectively reduced alkali burn-induced CNV, which was related to the RAP1/MEK/ERK pathway. NTD could be an effective treatment strategy for CNV post-alkali injury.