title: Carbon monoxide liberated from carbon monoxide-releasing molecule exerts an anti-inflammatory effect on dextran sulfate sodium-induced colitis in mice.
abstract: BACKGROUND
  Endogenous carbon monoxide (CO) is one of the three products of heme degradation by heme oxygenase-1 (HO-1) and exerts novel anti-inflammatory and anti-apoptotic effects as a gaseous second messenger. The purpose of this investigation was to determine whether exogenous CO could modulate intestinal inflammation.
  
  
  METHODS
  Acute colitis was induced with 2% DSS in male C57BL/6 mice. CO-releasing molecule-2 (CORM-2; tricarbonyldichlororuthenium(II) dimer) was intraperitoneally administered twice daily and the disease activity index (DAI) was determined. We measured tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration, and the production of keratinocyte chemoattractant (KC) and tumor necrosis factor-α (TNF-α) protein in the intestinal mucosa. In an in-vitro study, young adult mouse colonic epithelial (YAMC) cells were incubated with TNF-α, and KC mRNA/protein expression and nuclear translocation of nuclear factor-kappa B (NF-κB) were measured with or without CORM-2 treatment.
  
  
  RESULTS
  After DSS administration, DAI score increased in a time-dependent manner, and this increase was ameliorated by CORM-2 treatment. Increases in MPO activity and in the production of KC and TNF-α after DSS administration were significantly inhibited by CORM-2. TNF-α-induced KC production in YAMC cells was also inhibited by CORM-2 treatment. Further, nuclear translocation of NF-κB in YAMC cells was inhibited by CORM-2.
  
  
  CONCLUSIONS
  CORM-liberated CO significantly inhibited inflammatory response in murine colitis by inhibition of cytokine production in the colonic epithelium. These results suggest that CO could become a new therapeutic molecule for inflammatory bowel disease.
authors.affiliation: Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Takagi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Uchiyama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ikuhiro
authors.initials: I
authors.lastname: Hirata
authors.forename: Katsura
authors.initials: K
authors.lastname: Mizushima
authors.forename: Hisato
authors.initials: H
authors.lastname: Tsuboi
authors.forename: Natsuko
authors.initials: N
authors.lastname: Hayashi
authors.forename: Osamu
authors.initials: O
authors.lastname: Handa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yagi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kokura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichikawa
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000627:therapeutic use; D002248:Carbon Monoxide / Q000378:metabolism / Q000627:therapeutic use*; D002630:Chemotactic Factors / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002630:Chemotactic Factors; D009942:Organometallic Compounds; D014409:Tumor Necrosis Factor-alpha; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D016264:Dextran Sulfate; D009195:Peroxidase