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      Rebamipide promotes lacrimal duct epithelial cell survival via protecting barrier function

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          Abstract

          Nasolacrimal duct obstruction (NLDO) is thought to be due to inflammation and fibrosis of lacrimal duct epithelial cells (LDECs). Here we investigated the effect of rebamipide, a drug that is used for the protection of the mucosa and the treatment of gastritis and gastroduodenal ulcers, on LDECs, both in vitro and in vivo. In this study, LDECs were cultured from rabbit lacrimal duct tissues, and the barrier function of LEDCs was examined in vitro via transepithelial electrical resistance (TER) measurement, with or without interleukin (IL)-6 and/or rebamipide. For the in vivo examination, benzalkonium chloride (BAC) was injected into the rabbit lacrimal ducts, followed by the application of rebamipide or a placebo vehicle alone. The results of the in vitro examination revealed a significant decrease in TER in the group treated with IL-6 alone compared with the placebo-vehicle group ( p < 0.05) and the group treated with IL-6 and rebamipide ( p < 0.01). The results of the in vivo examination revealed that the infiltration of neutrophils under the basement membrane and the disruption of tight junction proteins with BAC injection and rebamipide attenuates the disturbance of tissue construction. These results suggest that rebamipide protects LDECs via an anti-inflammatory effect and preserves the barrier function of those cells.

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          Most cited references20

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          Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients.

          Conjunctival and Tenon's capsule biopsies from two patient groups were quantitatively analyzed by light microscopy. Group A consisted of 20 patients with a primary glaucoma for whom surgery was a planned primary treatment modality. Group B was comprised of 20 patients with a primary glaucoma who had received at least two types of antiglaucoma topical medication, for a minimum of 1 year (mean, 7.7 years) before surgery. All slides were examined by two masked observers. A significant increase in the number of macrophages, lymphocytes, mast cells, and fibroblasts in the conjunctiva and Tenon's capsule and a significant decrease in the number of epithelial goblet cells were seen in the group that received long-term drop therapy. These results suggest that exhaustive medical therapy, before surgery is offered, increases the number of tissue inflammatory cells. It is possible this may enhance the risk of external bleb scarring and filtration surgery failure.
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            Primary acquired nasolacrimal duct obstruction. A clinicopathologic report and biopsy technique.

            Primary acquired nasolacrimal duct obstruction (PANDO) of adults is a clinical syndrome of unknown cause, and the histopathology of the nasolacrimal duct has not been substantially studied. A technique of excisional biopsy of the soft tissue contents within the nasolacrimal canal during external dacryocystorhinostomy (DCR) is presented. No complications were associated with the biopsy technique in 14 cases. Two cases of lacrimal obstruction secondary to sarcoidosis and leukemia were discovered in biopsies of patients with the clinical syndrome of PANDO, demonstrating the value of routine biopsy during DCR. Biopsies revealed a spectrum of changes that correlated with duration of symptoms. Early cases revealed active chronic inflammation along the entire length of the narrowed nasolacrimal duct. Intermediate cases revealed focal resolution of the inflammatory process with fibrosis, while late cases showed fibrous obliteration of the entire duct. Although the first event in primary acquired nasolacrimal duct obstruction remains uncertain, clinicopathologic correlation suggests that compression of the duct by inflammatory infiltrates and edema precedes clinical chronic dacryocystitis.
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              Corneal Alternations Induced by Topical Application of Benzalkonium Chloride in Rabbit

              Benzalkonium chloride (BAC) is the most common preservative in ophthalmic preparations. Here, we investigated the corneal alternations in rabbits following exposure to BAC. Twenty-four adult male New Zealand albino rabbits were randomly divided into three groups. BAC at 0.01%, 0.05%, or 0.1% was applied twice daily to one eye each of rabbits for 4 days. The contralateral untreated eyes were used as control. Aqueous tear production and fluorescein staining scores of BAC-treated eyes were compared with those of controls. The structure of the central cornea was examined by in vivo confocal microscopy. Expression of mucin-5 subtype AC (MUC5AC) in conjunctiva was detected by immunostainig on cryosections. Corneal barrier function was assessed in terms of permeability to carboxy fluorescein (CF). The distribution and expression of ZO-1, a known marker of tight junction, and reorganization of the perijunctional actomyosin ring (PAMR) were examined by immunofluorescence analysis. Although there were no significant differences between control and BAC-treated eyes in Schirmer scores, corneal fluorescein scores and the number of conjunctival MUC5AC staining cells, in vivo confocal microscopy revealed significant epithelial and stromal defects in all BAC-treated corneas. Moreover, BAC at 0.1% resulted in significant increases in central corneal thickness and endothelial CF permeability, compared with those in control eyes, and endothelial cell damage with dislocation of ZO-1 and disruption of PAMR. Topical application of BAC can quickly impair the whole cornea without occurrence of dry eye. A high concentration of BAC breaks down the barrier integrity of corneal endothelium, concomitant with the disruption of PAMR and remodeling of apical junctional complex in vivo.
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                Author and article information

                Contributors
                htanakan@koto.kpu-m.ac.jp
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                3 February 2020
                3 February 2020
                2020
                : 10
                : 1641
                Affiliations
                [1 ]ISNI 0000 0001 0667 4960, GRID grid.272458.e, Department of Ophthalmology, , Kyoto Prefectural University of Medicine, ; Kyoto, Japan
                [2 ]ISNI 0000 0001 0667 4960, GRID grid.272458.e, Department of Frontier Medical Science and Technology for Ophthalmology, , Kyoto Prefectural University of Medicine, ; Kyoto, Japan
                Author information
                http://orcid.org/0000-0002-9756-0236
                Article
                58314
                10.1038/s41598-020-58314-x
                6997454
                32015381
                f835fcbd-5abf-4e94-9da2-89cd6a218972
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 June 2019
                : 9 January 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100007132, Otsuka Pharmaceutical (Otsuka Pharmaceutical Co., Ltd.);
                Categories
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                © The Author(s) 2020

                Uncategorized
                cell biology,diseases
                Uncategorized
                cell biology, diseases

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