Macroscopic, microscopic and biochemical characterisation of spontaneous colitis in a transgenic mouse, deficient in the multiple drug resistance 1a gene

Abstract

4Biostatistics and Reporting, Sandwich, Kent 1 A novel animal model of spontaneous colonic inflammation, the multiple drug-resistant (mdr1) a À/À mouse, was identified by Panwala and colleagues in 1998. The aim of our study was to further characterise this model, specifically by measuring cytokines that have been implicated in inflammatory bowel disease (IBD) (IL-8 and IFN-g) in the colon/rectum of mdr1a À/À mice, and by determining the sensitivity of these, together with the macroscopic, microscopic and disease signs of colitis, to dexamethasone (0.05, 0.3 and 2 mg kg À1 subcutaneously (s.c.) daily for 7 days). 2 All mdr1a À/À mice had microscopic evidence of inflammation in the caecum and colon/rectum, while control mice with the same genetic background did not. Significant increases in colon/rectum and caecal weights and also in cytokine levels (both IFN-g and IL-8) in homogenised colon/rectum were observed in mdr1a À/À mice compared to mdr1a þ / þ mice. 3 Dexamethasone reduced the increases in tissue weights and also microscopic grading of colitis severity, but had no effect on IFN-g or IL-8. 4 This study supports the similarity of the gastrointestinal inflammation present in mdr1a À/À mice to that of human IBD, in particular Crohn's disease. This has been demonstrated at the macroscopic and microscopic levels, and was supported further by elevations in colonic levels of IFN-g and IL-8 and the disease signs observed. The incidence of colitis was much higher than previously reported, with all mice having microscopic evidence of colitis. The limited variance between animals in the parameters measured suggests that this model is reproducible.

MDR1 C3435T Polymorphism Is Predictive of Later Onset of Ulcerative Colitis in Japanese

“…They also indicated that infection with Helicobacter bilis induced diarrhea, weight loss, and IBDs in mdr1a-/-knockout mice. [14][15][16] Macroscopic, microscopic and biochemical examinations have confirmed that the colitis which develops in this model is similar to that of human IBDs, [14][15][16][17] and very recently, it has been confirmed that MDR1 mRNA expression in colonic tissues is down-regulated in patients with UC, but not with CD. 18) Next, MDR1 is located on chromosome 7 at q21.1, 19) which was one of the loci of susceptibility to…”

“…14-16) Macroscopic, microscopic and biochemical examinations have confirmed that the colitis which develops in this model is similar to that of human IBDs, [14][15][16][17] and very recently, it has been confirmed that MDR1 mRNA expression in colonic tissues is down-regulated in patients with UC, but not with CD.…”

“…13) Since mdr1a-/-knock-out mice are immunologically normal, the development of spontaneous colitis is presumably due to a defect in the barrier function of the intestinal epithelium. They also indicated that infection with Helicobacter bilis induced diarrhea, weight loss, and IBDs in mdr1a-/-knockout mice.14-16) Macroscopic, microscopic and biochemical examinations have confirmed that the colitis which develops in this model is similar to that of human IBDs, [14][15][16][17] and very recently, it has been confirmed that MDR1 mRNA expression in colonic tissues is down-regulated in patients with UC, but not with CD.18) Next, MDR1 is located on chromosome 7 at q21.1, 19) which was one of the loci of susceptibility toIBDs identified by a genome-wide analysis in an UK cohort, 6) and the linkage in this region has recently been confirmed by genome scan meta-analysis. 20) Finally, in 2003Finally, in -2005, independent groups in Germany and Scotland indicated that a silent genetic polymorphism in exon 26, C3435T, is associated with susceptibility to UC, but not to CD, 21,22) though the results are disputed.…”

The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice

“…Interestingly, saline treatment seems to activate the HPA axis in the abcb1ab (À/À) mice, but not in FVB/N controls. This may be due to the fact that abcb1ab (À/À) mice suffer from spontaneous colitis (Banner et al, 2004) and, therefore, could be more sensitive to the manipulation associated with two daily i.p. injections for 1 week.…”

Dysfunction in ABCB1A Has Only a Weak Effect on Susceptibility to Dextran Sulfate Sodium-Induced Colitis in SAM Strains

“…-/-) spontaneously develop colitis with characteristics including dysregulated epithelial cell growth and leukocytic infiltration into the lamina propria of the large intestine; 20 weeks is the average age at onset [1,2,4,7,10,15,16,20]. In a previous study, we found that a series of Senescence-Accelerated Mouse (SAM) strains, including SAMR1, SAMP1, and SAMP6, have a spontaneous loss-of-function mutation in the Abcb1a gene [24].…”