The effect of an inhibitor of matrix metalloproteinases on colonic inflammation in a trinitrobenzenesulphonic acid rat model of inflammatory bowel disease.
BACKGROUND
Recent publications have reported that matrix metalloproteinases (MMPs) are expressed in colonic tissue taken from ulcerative colitis and Crohn's disease patients.


OBJECTIVE
To evaluate the effects of a matrix metalloproteinase inhibitor, marimastat, on colonic inflammation in experimental colitis induced by trinitrobenzenesulphonic acid (TNBS)-ethanol in the rat.


METHODS
Rats were dosed (by mouth) for 7 days (b.d.) with either sulphasalazine (50 mg/kg), marimastat (40 mg/kg) or vehicle. TNBS-ethanol was administered rectally on the 4th day of dosing. On the last day of dosing, colons were removed and assessed for inflammation using myeloperoxidase activity, production of soluble TNFalpha (tumour necrosis factor alpha), clinical score and histological assessment. In addition, the bioavailability and effect of marimastat on a range of MMPs were assessed in-vitro.


RESULTS
In this study we have confirmed that marimastat is a broad spectrum MMPI with a bioavailability of 5%. TNBS rats dosed with sulphasalazine had a significantly lower (P < 0.05) myeloperoxidase activity, TNFalpha production and a markedly lower clinical score. Similarly, rats dosed with marimastat had a significantly lower (P < 0.05) myeloperoxidase activity and clinical score, but the TNFalpha production was not significantly reduced.


CONCLUSIONS
Dosing rats with TNBS-induced colitis using sulphasalazine or marimastat produced a significant reduction in tissue injury and inflammation.
Sykes
A P
AP
Biosciences Department, University of Hertfordshire, Hertfordshire, UK. a.p.sykes@herts.ac.uk
Bhogal
R
R
Brampton
C
C
Chander
C
C
Whelan
C
C
Parsons
M E
ME
Bird
J
J
D000818:Animals; D001682:Biological Availability; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; C100342:marimastat; D009195:Peroxidase; D020782:Matrix Metalloproteinases