INOS ablation promotes corneal wound healing via activation of Akt signaling

Ziwen Sun; Kunpeng Lu; Qing He; Yang Tang; Haoru Li; Emmanuel Eric Pazo; Lizhi Hu; Ruihua Wei

doi:10.1016/j.exer.2024.109886

INOS ablation promotes corneal wound healing via activation of Akt signaling

Exp Eye Res. 2024 Apr 5:243:109886. doi: 10.1016/j.exer.2024.109886. Online ahead of print.

Authors

Ziwen Sun¹, Kunpeng Lu², Qing He¹, Yang Tang³, Haoru Li¹, Emmanuel Eric Pazo¹, Lizhi Hu⁴, Ruihua Wei⁵

Affiliations

¹ Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 300070, Tianjin, China.
² Tianjin Eye Hospital, Tianjin Key Lab of Ophthalmology and Visual Science, 300070, Tianjin, China.
³ Qingdao State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong Academy of Medical Sciences, 266071, Qingdao, China.
⁴ Basic Medical College, Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, 300070, China. Electronic address: lizhihu@tmu.edu.cn.
⁵ Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, 300070, Tianjin, China. Electronic address: rwei@tmu.edu.cn.

PMID: 38583755
DOI: 10.1016/j.exer.2024.109886

Abstract

Corneal injury leads to impaired normal structure of the cornea. Improving the wound healing process in epithelial cells significantly contributes to ocular damage treatments. Here, we aimed to investigate the potential mechanisms of nitric oxide (NO) and its mediator, inducible nitric oxide synthase (iNOS), in the process of corneal wound healing. We established a corneal injury model of iNOS^-/- mice, and treated human corneal epithelial cell lines (HCE-2) with the iNOS inhibitor L-INL, with or without NO replenishment by supplying sodium nitroferricyanide dihydrate (SNP). Our findings showed that inhibition of NO/iNOS accelerated corneal repair, enhanced uPAR (a receptor protein indicating the migration ability), and improved epithelial cell migration. Furthermore, NO/iNOS ablation activated Akt phosphorylation, reduced neutrophil marker protein MPO expression, and downregulated the transcription of inflammation cytokines CXCL-1, CXCL-2, IL-1β, IL-6, and TNF-α. However, the protective effects of NO/iNOS inhibition are significantly reduced by NO replenishment when treated with SNP. Therefore, we confirmed that inhibiting NO/iNOS improved the corneal wound healing by facilitating epithelial cell migration and reducing inflammatory reactions, which might be related to the activation of the Akt signaling pathway.

Keywords: Akt signaling pathway; Corneal wound healing; Epithelial cell migration; Inducible nitric oxide synthase; Nitric oxide.