Abstract
BackgroundTopical application of β-blocker eye drops induces damage to the ocular surface in clinical. However, the mechanism involved remains incompletely understood. The purpose of this study was to investigate the influence and mechanism of β-blocker eye drops on corneal epithelial wound healing.MethodsCorneal epithelial wound healing models were constructed by epithelial scraping including in the limbal region and unceasingly received eye drops containing 5 mg/mL β-blocker levobunolol, β1-adrenoceptor (β1AR)-specific antagonist atenolol or β2-adrenoceptor (β2AR)-specific antagonist ICI 118, 551. For the migration assay, the murine corneal epithelial stem/progenitor cells (TKE2) were wounded and subsequently incubated with levobunolol, atenolol, or ICI 118, 551. The proliferation and colony formation abilities of TKE2 cells treated with levobunolol, atenolol, or ICI 118, 551 were investigated by CCK-8 kit and crystal violet staining. The differentiation marker Cytokeratin 3 (CK3), the stem cell markers-Cytokeratin 14 (CK14) and Cytokeratin 19 (CK19), and corneal epithelium regeneration-related signaling including in Ki67 and the phosphorylated epithelial growth factor receptor (pEGFR) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) were assessed by immunofluorescence staining.ResultsLevobunolol and ICI 118, 551 impaired corneal wound healing, decreased the expressions of CK3, CK14, and CK19 after limbal region scraping in vivo and reduced the migration and proliferation of TKE2 in vitro, whereas atenolol had no significant effect. Moreover, levobunolol and ICI 118, 551 inhibited corneal wound healing by mediating the expression of Ki67, and the phosphorylation of EGFR and ERK1/2 in the limbal and regenerated corneal epithelium.Conclusionβ-blocker eye drops impaired corneal wound healing by inhibiting the β2AR of limbal stem cells, which decreased corneal epithelial regeneration-related signaling. Therefore, a selective β1AR antagonist might be a good choice for glaucoma treatment to avoid ocular surface damage.
Highlights
Topical application of β-blocker eye drops induces damage to the ocular surface in clinical
We investigated the effects of the anti-glaucoma agent levobunolol on corneal limbal stem cells by establishing corneal wound healing models with the entire corneal epithelium, including limbal region scrape
Non‐selective β‐blocker levobunolol impairs corneal wound healing through limbal stem cells in mice To assess the influence of β-blocker eye drops on corneal wound healing, we removed the central or the entire corneal epithelium including the limbal region by marking with 2.5 or 3 mm trephine
Summary
Topical application of β-blocker eye drops induces damage to the ocular surface in clinical. The purpose of this study was to investigate the influence and mechanism of β-blocker eye drops on corneal epithelial wound healing. Toxic keratitis involves complex clinical manifestations, which is difficult to differentiate from other ocular surface diseases, and requires a careful medical history and clinical examination. The treatment of glaucoma is long and is usually combined with other drugs. These factors increase the risk of toxic keratitis. Research on drug toxicity may help prevent permanent damage to the ocular surface
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