title: Rebamipide ameliorates indomethacin-induced small intestinal injury in rats via the inhibition of matrix metalloproteinases activity.
abstract: OBJECTIVE
  The pathogenesis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal lesions remains unclear, although it is considered to be quite different from that of upper gastrointestinal tract ulcers due to the absence of acid and the presence of bacteria and bile in the small intestine. The aim of this study was to characterize specific gene expression profiles of intestinal mucosa in indomethacin-induced small intestinal injury, and to investigate the effects of rebamipide on the expression of these genes.
  
  
  METHODS
  Intestinal injury was induced in male Wistar rats by subcutaneous administration of indomethacin. Total RNA of the intestinal mucosa was extracted 24 h after indomethacin administration, gene expression was investigated using microarray analysis, and the identified genes were confirmed by real-time polymerase chain reaction (PCR). In addition, we investigated whether the treatment with rebamipide altered the expression of these identified genes.
  
  
  RESULTS
  The administration of indomethacin induced small intestine injuries, and these lesions were significantly inhibited by the treatment with rebamipide. Microarray analysis showed that the genes for several matrix metalloproteinases (MMPs) and several chemokine-related genes were significantly upregulated, and metallothionein 1a (MT1a) was downregulated in the intestinal mucosa after administration of indomethacin. The expressions of these genes were reversed by the treatment with rebamipide.
  
  
  CONCLUSIONS
  These data suggest that MMPs, chemokines, and MT1a may play an important role in the intestinal mucosal injury induced by indomethacin. In particular, the inhibition of MMP genes and chemokine-related genes by rebamipide may be important for the therapeutic effect against NSAIDs-induced small intestinal injury.
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Doshisha University, Kyoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamada
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Takagi
authors.forename: Katsura
authors.initials: K
authors.lastname: Mizushima
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Horie
authors.forename: Kohei
authors.initials: K
authors.lastname: Fukumoto
authors.forename: Ken
authors.initials: K
authors.lastname: Inoue
authors.forename: Akihito
authors.initials: A
authors.lastname: Harusato
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Uchiyama
authors.forename: Osamu
authors.initials: O
authors.lastname: Handa
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichikawa
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects*; D007279:Injections, Subcutaneous; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000293:injuries* / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020782:Matrix Metalloproteinases / Q000378:metabolism* / Q000502:physiology; D008668:Metallothionein / Q000037:antagonists & inhibitors / Q000502:physiology; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018925:Chemokines; C530099:MT1A protein, human; D061965:Matrix Metalloproteinase Inhibitors; D015363:Quinolones; D008668:Metallothionein; D020782:Matrix Metalloproteinases; C052785:rebamipide; D000409:Alanine; D007213:Indomethacin