Abstract
We report on the development of a method for repeated monitoring of mucosal permeability that allows assessment of the severity of colitis and evaluation of treatment efficacy in HLA-B27 transgenic rats. We determined the extent to which intestinal permeability related to stool condition, colon weight, and histological pathology in precolitic and diseased rats up to 29 weeks old. Intestinal permeability was measured by the urinary excretion of iodixanol at 24 h after oral administration. Mean permeability values increased significantly with age in HLA-B27 rats but remained decreased in the background strain Fischer-344 (F-344) control animals. Macroscopic evaluation of HLA-B27 rat colons between 20 and 24 weeks old showed colonic thickening with colonic wet weights increased from 3.4 ± 0.13 mg/kg b.wt. in F-344 rats to 6.79 ± 0.73 mg/kg b.wt. (p < .05) in HLA-B27 rats. Histological examination of HLA-B27 rat colons confirmed the colonic inflammation as a chronic active mononuclear cell infiltrate. The increase in colon weight was associated with an increase in permeability: 1.16 ± 0.17 mg iodixanol versus 5.37 ± 1.3 mg of iodixanol in F-344 and HLA-B27 rats, respectively. Three weeks treatment of HLA-B27 rats with cyclosporin A, but not sulfasalazine, showed a dose-dependent decrease in mucosal permeability and colon weight. Neither treatment improved stool condition. We conclude that the measurement of intestinal permeability by iodixanol excretion is a useful biochemical marker that is associated with increases in colonic weight and histological evaluation of inflammation. These data indicate that this technique may be valuable for diagnostic and evaluation purposes in preclinical models of inflammatory bowel disease.
Footnotes
-
Send reprint requests to: Dr. Steven W. Kerr, Department of Pharmacology, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd., Ridgefield, CT 06877.
-
↵1 Present address: Huntingdon Life Sciences, P.O. Box 2360, Mettlers Rd., East Millstone, NJ 08875.
-
↵2 Present Address: Danbury Hospital, Department of Pathology, 24 Hospital Ave., Danbury, CT 06810.
- Abbreviations:
- IBD
- inflammatory bowel disease
- mgI
- milligrams iodixanol
- CsA
- cyclosporin A
- F-344
- Fischer-344
- Received March 3, 1999.
- Accepted June 19, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|