Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults.
Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults.
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DOI：
10.1002/ibd.20824
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发表时间：
2009-05
影响因子：
4.9
通讯作者：
Lorenz, Robin G.
中科院分区：
文献类型：
--
作者：
Staley, Elizabeth M.;Schoeb, Trenton R.;Lorenz, Robin G.
P-glycoprotein (P-gp), the product of the multi-drug 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. 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 non-steroidal anti-inflammatory (NSAID) drug which inhibits prostaglandin production, and initiates colitis in IL10 deficient animals. Helicobacter bilis (H.bilis) is a known mediator of bacterial induced colitis. 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. 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.
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