PURPOSE. Extended contact lens (CL) wear predisposes the wearer to Pseudomonas aeruginosa infection of the cornea, but the mechanism involved remains incompletely understood. The purpose of this study was to investigate the role of the stress hormone norepinephrine (NE) in the pathogenesis of CL-induced P. aeruginosa keratitis. METHODS. A total 195 adult C57BL/6 mice were used in this study. Corneal NE content was measured after 48 hours of sterile CL wear in mice. The effect of NE on P. aeruginosa adhesion and biofilm formation on the CL surface was examined in vitro. Moreover, mouse eyes were covered with P. aeruginosa-contaminated CLs, and either 500-μM NE was topically applied or the eyes were subconjunctivally injected with 100 μg of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to deplete local NE. Clinical scores, neutrophil infiltration, proinflammatory cytokine levels, and bacterial load on the corneas and CLs were evaluated. RESULTS. Corneal NE content was elevated with extended CL wear in mice. In vitro, NE promoted the adhesion and biofilm formation of P. aeruginosa on the CL surface. In mice, topical application of NE aggravated P. aeruginosa infection, accompanied with increased clinical scores, neutrophil infiltration, proinflammatory cytokine expression, and bacterial burden on the corneas and CLs. However, pre-depletion of local NE with DSP-4 significantly alleviated the severity of P. aeruginosa keratitis. CONCLUSIONS. Extended CL wear elevates corneal NE content, which promotes the pathogenesis of CL-induced P. aeruginosa keratitis in mice. Targeting NE may provide a potential strategy for the treatment of CL-related corneal infection caused by P. aeruginosa.
Background Topical 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. Methods Corneal 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. Results Levobunolol 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. Conclusion β-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.
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