Macroscopic, microscopic and biochemical characterisation of spontaneous colitis in a transgenic mouse, deficient in the multiple drug resistance 1a gene.
1 A novel animal model of spontaneous colonic inflammation, the multiple drug-resistant (mdr1) a(-/-) 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-gamma) in the colon/rectum of mdr1a(-/-) 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(-1) subcutaneously (s.c.) daily for 7 days). 2 All mdr1a(-/-) 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-gamma and IL-8) in homogenised colon/rectum were observed in mdr1a(-/-) mice compared to mdr1a(+/+) mice. 3 Dexamethasone reduced the increases in tissue weights and also microscopic grading of colitis severity, but had no effect on IFN-gamma or IL-8. 4 This study supports the similarity of the gastrointestinal inflammation present in mdr1a(-/-) 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-gamma 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.
Banner
Katharine H
KH
Pfizer Global Research and Development, Discovery Biology, Sandwich, Kent, UK. kathy_banner@sandwich.pfizer.com
Cattaneo
Christophe
C
Le Net
Jean-Loic
JL
Popovic
Aleksandar
A
Collins
David
D
Gale
Jeremy D
JD
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D044082:Citrobacter rodentium / Q000302:isolation & purification; D003092:Colitis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D003106:Colon / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000627:therapeutic use; D005243:Feces / Q000382:microbiology; D016998:Helicobacter / Q000302:isolation & purification; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D012007:Rectum / Q000473:pathology
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D011506:Proteins; D003907:Dexamethasone; C095122:multidrug resistance protein 3