Rebamipide alleviates radiation-induced colitis through
improvement of goblet cell differentiation in mice
Janet Lee,* Jae kyung Myung,*
Won-Suk Jang,* Sun-Joo Lee,*
Hyunwook Myung,* Changsun Lee,* Hyewon Kim,* Seung-Sook Lee,*
Young-Woo Jin* and Sehwan Shim*
*Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, and
Department of Pathology, Korea Cancer Center
Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
colitis, goblet cells, radiation, rebamipide.
Accepted for publication 10 October 2017.
Dr Sehwan Shim and Dr Hyosun Jang,
Laboratory of Radiation Exposure and
Therapeutics, National Radiation Emergency
Medical Center, Korea Institute of Radiological
and Medical Sciences, 75 Nowon-ro, Nowon-
gu, Seoul 01812, Korea.
Financial support: This study was supported by
grant 1501007 from Nuclear Safety and Security
Commission (NSSC) and as well as a grant from
Korea Institute of Radiological and Medical
50535-2017) funded by the Korea Government
Ministry of Science, ICT, & Future Planning.
These authors contributed to this work equally.
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 in-
vestigate whether radiation-induced colonic injury could be alleviated by rebamipide.
Methods: This study orally administered rebamipide for 6 days to mice, which were sub-
jected 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. Addition-
ally, 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.
Radiotherapy and accidental exposure to ionizing radiation cause
severe damage to healthy tissue. The gastrointestinal tract is a
radiation-sensitive organ, and gastrointestinal complications of
radiation are collectively referred to as gastrointestinal acute radi-
ation syndrome (GI-ARS).
GI-ARS can cause a clinical problem,
called acute radiation enteritis, which involves inﬂammation,
edema, epithelial barrier impairment, ulceration, a decrease in
mitotic activity, and crypt defects in the gastrointestinal tract.
Bacterial translocation is deﬁned as the passage of viable endoge-
nous bacteria and endotoxins from the gastrointestinal tract to ex-
traintestinal sites such as the mesenteric lymph node (mLN)
complex, liver, spleen, kidney, and bloodstream.
and bacteremia are critical events in the pathogenesis of GI-
ARS, and the colon is the primary source of endotoxins, which
thus highlights the importance of this tissue’s injury during radia-
Goblet cells are columnar epithelial cells specializing in the
secretion of high-molecular-weight glycoproteins, called mucins,
which consist of a protein core, rich in threonine, proline, or serine
residues, supplemented with an O-linked oligosaccharide.
cells play a pivotal role in epithelial defense against luminal stim-
ulants and pathogens.
Mucin 2 (MUC2), synthesized by goblet
cells, is the predominant structural component of the intestinal mu-
cus layer that functions as a barrier to protect the epithelium.
Furthermore, it is well known that goblet cells decrease in number
or are depleted in the inﬂamed mucosa of animal models of colitis
and in patients with inﬂammatory bowel disease.
the pathophysiological changes occurring in goblet cells in irradi-
ated colonic tissue are still unknown.
Rebamipide is a quinolone derivative with anti-inﬂammatory
activity and is widely used as an antigastric ulcer drug.
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,
promotes the proliferation
Journal of Gastroenterology and Hepatology 33 (2018) 878–886
© 2017 The Authors Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd
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