Effect of OPC-12759 on EGF receptor activation, p44/p42 MAPK activity, and secretion in conjunctival goblet cells

Shinohara

Experimental and Therapeutic Medicine

et al. 2017

Abstract. It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor (EGFR) induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. The number of goblet cells was significantly higher in the rebamipide group compared with the non-rebamipide group (P= 0.0367). There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. Immunohistochemistry revealed that EGFR levels in the lid wiper epithelial cells were significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0237). These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy.

Section: Discussionsupporting

confidence: 82%

“…Several previous studies have demonstrated that transactivation of EGFR enhances mucin secretion in rat conjunctival goblet cells (14)(15)(16). Furthermore, Rios et al (16) demonstrated that topical rebamipide stimulates mucin secretion from cultured goblet cells via the EGFR-signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva

Shinohara

Experimental and Therapeutic Medicine

et al. 2017

J of Gastro and Hepatol

“…17 It is known that the application of topical rebamipide increases both the number of goblet cells and the level of mucin-like substances in the bulbar conjunctiva of rabbits, 18,19 promotes the proliferation of cultured rat conjunctival goblet cells, 20 and induces the mucin secretion from cultured conjunctival goblet cells of rats. 21 Application of rebamipide alleviates the inflammation in the small intestine through its anti-inflammatory effects and activation of the Wnt/β-catenin pathway. 22,23 In this study, because goblet cells play important roles in intestinal barrier damage, we investigated whether rebamipide could attenuate the radiation-induced colitis by inducing differentiation of goblet cells in mice model and human colonic epithelial cell line.…”

Section: Introductionmentioning

confidence: 99%

Rebamipide alleviates radiation‐induced colitis through improvement of goblet cell differentiation in mice

Jang

Park

Lee

et al. 2018

Background and Aim: Radiation-induced colitis is a common clinical problem associated with radiotherapy and accidental exposure to ionizing radiation. Goblet cells play a pivotal role in the intestinal barrier against pathogenic bacteria. Rebamipide, an anti-gastric ulcer drug, has the effects to promote goblet cell proliferation. The aim of this study was to investigate whether radiation-induced colonic injury could be alleviated by rebamipide. Methods: This study orally administered rebamipide for 6 days to mice, which were subjected to 13 Gy abdominal irradiation, to evaluate the therapeutic effects of rebamipide against radiation-induced colitis. To confirm the effects of rebamipide on irradiated colonic epithelial cells, this study used the HT29 cell line. Results: Rebamipide clearly alleviated the acute radiation-induced colitis, as reflected by the histopathological data, and significantly increased the number of goblet cells. The drug also inhibited intestinal inflammation and protected from bacterial translocation during acute radiation-induced colitis. Furthermore, rebamipide significantly increased mucin 2 expression in both the irradiated mouse colon and human colonic epithelial cells. Additionally, rebamipide accelerated not only the recovery of defective tight junctions but also the differentiation of impaired goblet cells in an irradiated colonic epithelium, which indicates that rebamipide has beneficial effects on the colon. Conclusions: Rebamipide is a therapeutic candidate for radiation-induced colitis, owing to its ability to inhibit inflammation and protect the colonic epithelial barrier.

Invest. Ophthalmol. Vis. Sci.

“…Topical rebamipide reportedly reduces UV-B-induced corneal oxidative damage and surface irregularity in mice 16 and improves the ocular surface by inducing mucin-like secretion from the rat keratoconjunctival epithelium. 17 The conjunctival epithelium is a nonkeratinized, stratified, squamous epithelium that also harbors mucin-secreting goblet cells. [17][18][19] Goblet cell loss has been reported to be associated with many types of dry eyes, especially in keratoconjunctivitis sicca.…”

mentioning

confidence: 99%

“…17 The conjunctival epithelium is a nonkeratinized, stratified, squamous epithelium that also harbors mucin-secreting goblet cells. [17][18][19] Goblet cell loss has been reported to be associated with many types of dry eyes, especially in keratoconjunctivitis sicca.…”

mentioning

confidence: 99%

The Role of 2% Rebamipide Eye Drops Related to Conjunctival Differentiation in Superoxide Dismutase-1 (Sod1) Knockout Mice

Kojima

Şimşek

Igarashi

et al. 2018

Citation: Kojima T, Simsek C, Igarashi A, et al. The role of 2% rebamipide eye drops related to conjunctival differentiation in superoxide dismutase-1 (Sod1) knockout mice. Invest Ophthalmol Vis Sci. 2018;59:1675-1681. https://doi.org/10.1167/iovs.17-23213 PURPOSE. The superoxide dismutase-1 knockout (Sod1 À/À ) mouse is an age-related dry eye mouse model. We evaluated the role of 2% rebamipide ophthalmic solution on the conjunctiva and ocular surface alterations in Sod1 À/À mice. METHODS.Rebamipide eye drops (2%) were instilled in six 50-week-old male Sod1 À/À mice and six C57BL/6 strain wild-type (WT) male mice four times a day for 2 weeks. Aqueous tear secretion quantity and tear film breakup time measurements as well as vital stainings were performed. Immunohistochemistry staining of the conjunctiva was performed using SAM pointed domain-containing ETS transcription factor (SPDEF), transglutaminase-1, and involucrin antibodies. Quantitative RT-PCR was carried out to study mRNA expression of the same markers.RESULTS. The mean tear quantities showed no significant changes in both mice strains after treatment (P ¼ 0.24). The mean tear film breakup time (P ¼ 0.003) and vital staining scores significantly improved in the Sod1 À/À mice after treatment. Treatment with 2% rebamipide eye drops significantly decreased the corneal fluorescein (P ¼ 0.0093) and Rose Bengal (P ¼ 0.002) staining scores in the Sod1 À/À mice. We showed a notable increase in SPDEF and a marked decrease in transglutaminase-1 and involucrin immunohistochemistry stainings, together with a significant increase in SPDEF (P ¼ 0.0003) and a significant decline in transglutaminase-1 (P ¼ 0.0072) and involucrin (P ¼ 0.009) mRNA expression after treatment in the Sod1 À/À mice.CONCLUSIONS. Topical use of 2% rebamipide drops was observed to improve conjunctival epithelial differentiation and suppress keratinization in the Sod1 À/À mice.