Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults.
BACKGROUND
P-glycoprotein (P-gp), the product of the multidrug resistance gene (MDR), is an ATP-dependent transmembrane pump, which is expressed in multiple cell lineages including epithelial and hematopoetic cells. The human MDR gene is located on chromosome 7 (7q21.1), a susceptibility loci for inflammatory bowel disease (IBD). A significant number of IBD patients carry mutations in this gene and P-gp-deficient FVB/N mice develop a severe spontaneous colitis, characterized by impaired intestinal barrier function and immune reactivity to intestinal bacterial antigens.


METHODS
In this work we explored the role of mouse strain, as well as environmental insults, on the development of colonic inflammation in the absence of P-gp. Among the induction methods utilized, dextran sodium sulfate (DSS) disrupts the intestinal epithelium, while piroxicam is a nonsteroidal antiinflammatory (NSAID) drug that inhibits prostaglandin production and initiates colitis in IL10-deficient animals. Helicobacter bilis is a known mediator of bacterial-induced colitis.


RESULTS
We demonstrate that crossing this mutation onto the C57BL/6 strain confers protection from spontaneous colitis. C57BL/6.mdr1a-deficient animals demonstrated increased histological inflammation, colonic shortening, fecal blood, and reduced body weight after 7 days of treatment with 2.25% DSS. C57BL/6.mdr1a-deficient mice treated with piroxicam or infected with H. bilis showed no weight loss, or alterations in colonic histology.


CONCLUSIONS
These data indicate that the effects of P-gp deficiency are significantly modulated by background strain influences, but that the epithelium continues to have increased susceptibility to chemical injury in the C57BL/6 model.
Staley
Elizabeth M
EM
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35243-2182, USA.
Schoeb
Trenton R
TR
Lorenz
Robin G
RG
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D003092:Colitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D004032:Diet; D004198:Disease Susceptibility; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016998:Helicobacter / Q000472:pathogenicity*; D016481:Helicobacter Infections / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010894:Piroxicam / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018435:ATP Binding Cassette Transporter, Subfamily B; D000894:Anti-Inflammatory Agents, Non-Steroidal; D012333:RNA, Messenger; D010894:Piroxicam; D016264:Dextran Sulfate; C095122:multidrug resistance protein 3