An orally active matrix metalloproteinase inhibitor, ONO-4817, reduces dextran sulfate sodium-induced colitis in mice.
OBJECTIVE
Over-expression of matrix metalloproteinases (MMPs) can accelerate tissue destruction and disrupt subsequent tissue repair. A dextran sulfate sodium (DSS) colitis model was established to examine the effects of MMP inhibition, by an orally active MMP inhibitor ONO-4847, on colonic inflammation.


METHODS
Acute colitis was induced in female BALB/c mice by giving 8% DSS orally in drinking water for 7 days. The animals were randomized into groups receiving different concentrations of ONO-4847 or vehicle by oral gavage every day. mRNA levels of 4 MMPs and a tissue inhibitor of MMP (TIMP-1) were measured by RT-PCR in intestinal tissue isolated from mice after DSS administration. Colonic mucosal injury and inflammation were evaluated clinically, biochemically, and histologically. The clinical disease activity index (DAI), including body weight loss, stool consistency, and blood in feces, was examined. Moreover, mucosal tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were determined by immunoassay.


RESULTS
The intestinal expression of MMP-3, -7, 9, and -12 and TIMP-1 mRNA was upregulated after DSS administration. Shortening of the colon was significantly reversed by ONO-4847 at a dose of 30 mg/kg. DAI in DSS-treated mice was significantly lower in the ONO-4847-treated mice compared with the control mice. Histological study also showed a reduced infiltration of inflammatory cells, especially neutrophils, and reducedmucosal cell disruption in ONO-4847-treated mice compared with the control mice. The increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by co-administration with ONO-4847. ONO-4847 also inhibited increases in the mucosal TNF-alpha and IFN-gamma content after DSS administration.


CONCLUSIONS
Improvements in DSS colitis in response to ONO-4847 suggest that activation of MMPs contributes to the initiation/amplification of colonic inflammatory injury by mechanisms including oxidative damage as well as enhancement of inflammatory cytokine release.
Naito
Y
Y
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, 602-8566, Kyoto, Kawaramachi-Hirokoji, Japan. ynaito@koto.kpu-m.ac.jp
Takagi
T
T
Kuroda
M
M
Katada
K
K
Ichikawa
H
H
Kokura
S
S
Yoshida
N
N
Okanoue
T
T
Yoshikawa
T
T
D000284:Administration, Oral; D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010647:Phenyl Ethers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012720:Severity of Illness Index; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D019715:Tissue Inhibitor of Metalloproteinase-1; D016264:Dextran Sulfate; D020782:Matrix Metalloproteinases