Anti-inflammatory effects of carbon monoxide-releasing molecule on trinitrobenzene sulfonic acid-induced colitis in mice.
OBJECTIVE
Recent findings indicate that carbon monoxide (CO) in non-toxic doses exerts a beneficial anti-inflammatory action in various experimental models. However, the precise anti-inflammatory mechanism of CO in the intestine remains unclear. Here, we assessed the effects of a novel water-soluble CO-releasing molecule, CORM-3, on trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice.


METHODS
To induce colitis, C57BL/6 male mice received an enema of TNBS. CORM-3 or its inactive compound, iCORM-3, were administered intraperitoneally, once immediately before, and twice daily after receiving an enema of TNBS. Three days after TNBS administration, the distal colon was removed, assessed for colonic damage and histological scores, polymorphonuclear leukocyte recruitment (tissue-associated myeloperoxidase, MPO activity), and TNF-α, IFN-γ and IL-17A expression (mRNA and protein levels in the colon mucosa). CD4(+) T cells isolated from murine spleens were stimulated with anti-CD3/CD28, in the presence or absence of CORM-3/iCORM-3. The cell supernatants were assessed for TNF-α and IFN-γ expression, 24 h following stimulation.


RESULTS
Colonic damage and histological scores were significantly increased in TNBS-induced mice compared to sham-operated mice. Tissue-associated MPO activity and expression of TNF-α, IFN-γ, and IL-17A in the colonic mucosa were higher in TNBS-induced colitis mice. The above changes were attenuated in CORM-3-treated mice. Further, CORM-3 was effective in reducing TNF-α and IFN-γ production in anti-CD3/CD28-stimulated CD4(+) T cells.


CONCLUSIONS
These findings indicate that CO released from CORM-3 ameliorates inflammatory responses in the colon of TNBS-challenged mice at least in part through a mechanism that involves the suppression of inflammatory cell recruitment/activation.
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, wtrfkd@koto.kpu-m.ac.jp.
Wataru
W
Fukuda
Tomohisa
T
Takagi
Kazuhiro
K
Katada
Katsura
K
Mizushima
Tetsuya
T
Okayama
Naohisa
N
Yoshida
Kazuhiro
K
Kamada
Kazuhiko
K
Uchiyama
Takeshi
T
Ishikawa
Osamu
O
Handa
Hideyuki
H
Konishi
Nobuaki
N
Yagi
Hiroshi
H
Ichikawa
Toshikazu
T
Yoshikawa
Gediminas
G
Cepinskas
Yuji
Y
Naito
Yoshito
Y
Itoh
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use; D002248:Carbon Monoxide / Q000737:chemistry / Q000627:therapeutic use*; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D009942:Organometallic Compounds / Q000737:chemistry / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity*
D000963:Antimetabolites; D016207:Cytokines; D009942:Organometallic Compounds; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase