Exacerbation of indomethacin-induced small intestinal injuries in Reg I-knockout mice.
Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal injuries are serious clinical events and a successful therapeutic strategy is difficult. Regenerating gene (Reg) I protein functions as a regulator of cell proliferation and maintains intercellular integrity in the small intestine. The aim of this study was to evaluate the role of Reg I in NSAID-induced small intestinal injuries. First, to examine the effect of Reg I deficiency on such injuries, indomethacin, a widely used NSAID, was injected subcutaneously into 10-wk-old male Reg I-knockout (Reg I(-/-)) and wild-type (Reg I(+/+)) mice twice with an interval of 24 h, after which the mice were euthanized. Small intestinal injuries were assessed by gross findings, histopathology, and contents of IL-1beta and MPO in the experimental tissues. Next, we investigated the therapeutic potential of Reg I in indomethacin-induced small intestinal injuries. Recombinant Reg I protein (rReg I) was administered to 10-wk-old male ICR mice, then indomethacin was administered 6 h using the same protocol as noted above, after which small intestinal injuries were assessed after euthanasia. Our results showed that Reg I(-/-) mice had a greater number of severe small intestinal lesions after indomethacin administration. Histological examinations of the small intestines from those mice revealed deep ulcers with prominent inflammatory cell infiltration, whereas the mucosal content of proinflammatory agents was also significantly increased. In addition, rReg I administration inhibited indomethacin-induced small intestinal injuries in ICR mice. In conclusion, Reg I may be useful as a therapeutic agent in NSAID-induced small intestinal injuries.
Imaoka
Hiroshi
H
Dept. of Gastroenterology and Hepatology, Shimane Univ., Izumo, Japan. hiroshi.imaoka.md@me.com
Ishihara
Shunji
S
Kazumori
Hideaki
H
Kadowaki
Yasunori
Y
Aziz
Md Monowar
MM
Rahman
Farzana Binte
FB
Ose
Takayuki
T
Fukuhara
Hiroyuki
H
Takasawa
Shin
S
Kinoshita
Yoshikazu
Y
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors; D007410:Intestinal Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051847:Lithostathine / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000494:pharmacology; D012720:Severity of Illness Index; D014456:Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control
D000894:Anti-Inflammatory Agents, Non-Steroidal; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D051847:Lithostathine; D011994:Recombinant Proteins; C497615:Reg1 protein, mouse; D007213:Indomethacin