Repeated measurement of intestinal permeability as an assessment of colitis severity in HLA-B27 transgenic rats.
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.
Kerr
S W
SW
Department of Pharmacology, Research and Development Center, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, USA.
Wolyniec
W W
WW
Filipovic
Z
Z
Nodop
S G
SG
Braza
F
F
Winquist
R J
RJ
Noonan
T C
TC
D000818:Animals; D015415:Biomarkers; D003092:Colitis / Q000175:diagnosis*; D003106:Colon / Q000473:pathology*; D003287:Contrast Media / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005243:Feces / Q000737:chemistry*; D015796:HLA-B27 Antigen / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000502:physiology; D008297:Male; D009929:Organ Size; D010539:Permeability; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D012460:Sulfasalazine / Q000627:therapeutic use; D013997:Time Factors; D014283:Triiodobenzoic Acids / Q000493:pharmacokinetics
D015415:Biomarkers; D003287:Contrast Media; D015796:HLA-B27 Antigen; D014283:Triiodobenzoic Acids; D012460:Sulfasalazine; D016572:Cyclosporine; C044834:iodixanol