Purpose To investigate the pathogenesis of cytomegalovirus (CMV)-associated anterior segment infection in immunocompetent hosts and evaluate the effects of ganciclovir and glucocorticoid treatment in management of the disease. Methods We used an inoculation model to reproduce CMV anterior segment infection in immunocompetent rats. Flow cytometry, cytokine analysis, histopathological sections, and quantitative polymerase chain reaction were performed to investigate the immune response after CMV infection. The effects of ganciclovir and glucocorticoid treatment were also assessed. Results Anterior chamber inoculation of CMV in rats provoked characteristic pathological features of human CMV anterior segment infection. The innate and adaptive immunity sequentially developed in an anterior segment after inoculation, and the elevation of intraocular pressure (IOP) was highly associated with ocular infiltration and inflammation. Early ocular immune response reduced virus DNA in the anterior segment and alleviated viral lymphadenopathy. Early intervention with ganciclovir enhanced the release of cytokines associated with T response and facilitated recruitment of NKT and T cells in drainage lymph nodes. Glucocorticoid treatment, alone or combined with ganciclovir, decreased elevation of IOP but also impeded DNA clearance. Conclusions The inoculation model reproduced characteristic pathological features of human CMV anterior segment infection. The use of glucocorticoid in current practice may hinder viral clearance, and ganciclovir therapy can assist cytokine expression to combat the virus.
Endothelial rejection and a critical shortage of corneal transplants present an unmet medical need in corneal regeneration research area. Although basic fibroblast growth factor (bFGF) is a potent mitogenic factor for corneal ex vivo expansion, it is also a morphogen eliciting unfavorable endothelial‐mesenchymal transition (EnMT) of corneal endothelial cells. A pharmacological reagent that retains the beneficial proliferative effect while lacking the EnMT effect of bFGF would be of great potential in corneal regeneration. In present study, we demonstrated that bFGF not only activated the canonical fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase pathway, but also further upregulated matrix metalloproteinase activity to cleave N‐cadherin into N‐terminus and C‐terminus fragments, which activated the classical FGFR1 tyrosine kinase pathway and a cryptic β‐catenin pathway to affect corneal proliferation and EnMT, respectively. We generated the synthetic peptides resembling a critical motif in the ectodomain of N‐cadherin and found these peptides enhanced downstream proliferative signaling of FGFR1 but without seemingly EnMT effect. The potential of these peptides can be demonstrated on both ex vivo cell culture and in vivo rat cryo‐injury model. Our study indicated this peptidomimetic approach of N‐cadherin can stimulate corneal regeneration and offer a promising therapeutic option to treat corneal endothelial dysfunction.
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