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.