Purpose.: Although Epstein-Barr virus (EBV)–associated keratitis is rare, it can cause acute corneal necrosis and neovascularization. We aimed to examine the signaling mechanism by which EBV causes epithelial–mesenchymal transition (EMT) in human corneal epithelial cells (HCECs) in vitro. Methods.: The cellular response to EBV was assessed by real-time PCR, Western blot, migration assay, invasion assay, inhibitor assay, and ELISA assay. Results.: A model of EBV-induced EMT was established in HCECs. The EBV induced morphologic changes in the cells; the loss of epithelial markers E-cadherin, ZO-1, and β-catenin; and an increase in the mesenchymal markers N-cadherin, Vimentin, Snail, and TCF8/Zeb1. The EBV infection also led to the nuclear translocation of Snail and TCF8/Zeb1; enhanced the secretion of IL-6, IL-8, VEGF, TGF-β1, TNF-α, and MCP-1; and upregulated the expression of MMP2 and MMP9. The EBV-infected HCECs exhibited increased migration and invasiveness compared to uninfected HCECs. We measured the involvement of Syk, Src, PI3K/Akt, and Erk signaling, but not Smad, in EMT by EBV-induced TGF-β1. We demonstrated that treatment with TGF-β1, TGF-β receptors, Syk, or Src inhibitor blocked TGF-β1, Syk, or Src signaling activation, and EMT development by EBV. Moreover, these inhibitors prevented PI3K/Akt and Erk activation. Conclusions.: An EBV infection in HCECs can lead to a mesenchymal fibroblast-like morphology, and cause EMT through the activation of PI3K/Akt and Erk by TGF-β1–mediated Syk and Src signaling. This phenomenon may have implications for EBV-associated keratitis and molecular approaches to treatment.

Background Endonasal dacryocystorhinostomy (DCR) has been widely used to treat nasolacrimal duct obstruction. Here, we evaluated the anatomical advantages of the uncinate process as a landmark and to study the effect of unciformectomy on success rate and complications of endonasal DCR . Methods In total, 288 eyes of 265 adult patients who underwent endonasal DCR between January 2003 and February 2010 were reviewed retrospectively. The eyes were classified into two groups, according to whether unciformectomy was performed or not. All surgical procedures and surgical indications were the same except unciformectomy and endonasal DCR was performed by one surgeon. Unciformectomy was performed by resecting the anterior part of uncinate process. Results One hundred and eighty-six eyes of 168 patients received endonasal DCR with unciformectomy, and 102 eyes of 97 patients received endonasal DCR alone. The average success rate of endonasal DCR with unciformectomy was 97.8 % and that of endonasal DCR alone was 90.2 %, with statistically significant difference (Student's t-test, p-value < 0.05). There were 14 eyes with post-operative nasolacrimal obstruction, caused by granuloma in five eyes, intranasal synechia in two eyes, membranous obstruction in six eyes, and canalicular stenosis in one eye. There were no serious complications such as orbital fat prolapse, cerebrospinal fluid leak, or delayed hemorrhage. Conclusions Anterior resection of the uncinate process gives improved access to the lacrimal bone by exposing the medial aspect of the lacrimal fossa and forming the precise location of the osteotomy on the lacrimal bone during endonasal DCR. Thus, the uncinate process can be used as an anatomical landmark for endonasal DCR. The unciformian endonasal DCR improves operation success rate by allowing access to the large space of the nasal cavity and reducing the synechiae of the nasal cavity.

Purpose: The a-disintegrin-and-metalloprotease (ADAM) family proteins are widely expressed in the different layers of the retina throughout development. The effect of ADAM proteins on the epithelial-to-mesenchymal transition (EMT) in proliferative vitreoretinopathy (PVR) or AMD is yet to be elucidated. In this study we used Epstein-Barr virus (EBV)-transformed adult retinal pigment epithelial (ARPE) cells to investigate how sorafenib, a multikinase inhibitor, modulates ADAM proteins to control EMT. Methods: Epithelial to mesenchymal transition and related mechanisms in EBV-infected ARPE cells were determined by RT-PCR, Western blot, invasion assay, ELISA assay, and gene silencing with siRNA. Results: Mesenchymal-like ARPE/EBV cells exhibited considerably increased cellular migration and invasion compared with ARPE cells and produced EMT-related cytokines. Sorafenib significantly inhibited production of TGF-β1, VEGF, IL-6, IL-8, MCP-1, and TNF-α and blocked the activation of migration-related signaling molecules, such as HIF-1α, p-STAT3, MMP2, and Ang-1. The expression of mature ADAM10, ADAM17, and cleaved Notch 1 proteins in ARPE/EBV cells was downregulated after treatment with sorafenib through the regulatory activity of nardilysin (NRD-1). Gene silencing of NRD-1 in ARPE/EBV cells attenuated secretion of EMT-related cytokines and expression of ADAM10 and 17 and upregulated epithelial markers. Conclusions: Sorafenib controls the mesenchymal characteristics of EBV-infected ARPE cells. Nardilysin and ADAM family proteins might be new targets for the prevention or control of EMT in retinal diseases.

Yang JW, et al. Korean J Ophthalmol. 2007 Mar;21(1):48-50. http://dx.doi.org/10.3341/kjo.2007.21.1.48

Objectives The clinical course of thyroid eye disease (TED) is heterogeneous and predicting patients who may develop the severe sequelae of the disease is difficult. In this study, we evaluated the longitudinal association between changes in serum thyroid-stimulating hormone (TSH) receptor antibody (TRAb) levels and course of disease activity and severity over time. Design This was a multicentre, prospective, observational study. Setting Fifteen tertiary care oculoplastic service centres in Korea. Participants Seventy-six patients with newly diagnosed TED were included and followed up for 12 months. Methods We evaluated clinical characteristics and serum TRAb levels at baseline, 6 and 12 months of TED diagnosis. Additionally, we analysed longitudinal associations between the serum TRAb levels and clinical activity score (CAS), no signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, sight loss (NOSPECS) score and proptosis. Results Thyroid-stimulating immunoglobulin (TSI) and TSH-binding inhibitory immunoglobulin (TBII) levels decreased during the 1-year follow-up, whereas disease activity measured using CAS decreased mainly in the first 6 months. Disease severity measured using NOSPECS score and proptosis remained unchanged. Moreover, inter-person differences in TBII levels were associated with CAS, NOSPECS score and proptosis over time, whereas inter-person differences in TSI levels were associated with NOSPECS score. Subgroup analysis of patients with a baseline CAS≥4 demonstrated that within-person changes in TSI levels affected the CAS and NOSPECS score. Conclusions Follow-up measurement of serum TSI and TBII levels may help evaluate TED prognosis and enable accurate clinical decision-making.

As a posterior ocular disease, wet age-related macular degeneration (WAMD) has been known to be related to vision loss, accompanying ocular complications. The intravitreous injection of VEGF antibodies has been reported to be an effective treatment to relieve symptoms of WAMD. However, the limitations of this treatment are high costs and invasiveness. For this reason, oral delivery route can be considered as a cost-effective way and the safest method to deliver drug molecules to the eyes. Accordingly, ursodeoxycholic acid (UDCA) was included in the oral formulation as the potential substance for the cure of WAMD in the animal model. Various pharmacological activities, such as antioxidant or anti-inflammatory effects, have been reported for UDCA and recent reports support the effects of UDCA in ocular treatment. However, due to poor water solubility and low pKa (around 5.0), it has been challenging to formulate aqueous solution of UDCA in the neutral pH range. In the present study, we confirmed the aqueous solubility of the oral UDCA formulation and performed a preclinical study, including pharmacokinetic profiling and WAMD model efficacy study in mice after oral administration of the drug solution. The results demonstrated that the formulation improved bioavailability of UDCA and efficiently delivered UDCA to the eye tissues after oral absorption. UDCA formulation was found to have inhibitory effects of choroidal neovascularization with a functional recovery in mice retinas. Taken together, our results suggest that the oral UDCA formulation could be used as a potent supplement for the cure of WAMD and related retinal diseases.