Differential susceptibility of multidrug resistance protein-1 deficient mice to DSS and TNBS-Induced colitis

The molecular mechanisms underlying inflammatory bowel diseases (IBD) are incompletely characterized. MRP-1, normally expressed in the large and small bowel epithelium, serves as a multidrug resistance protein. In this report we explored the role of MRP1 in IBD. Mrp1-deficient mice (mrp1(-/-)) were subjected to two different models of IBD. The mrp1(-/-) mice and wild-type (WT) mice showed equal induction of TNBS colitis, a hapten-induced T-cell mediated disease. However, in DSS colitis more severe disease was observed in mrp1(-/-) mice. In a survival study, mortality of mrp1(-/-) mice was higher. In nonlethal DSS colitis, the mean histological colitis score was significantly higher in mrp1(-)/- mice and showed particularly severe epithelial damage. Although endogenous LTB4 levels were significantly increased in mrp1(-/-) mice, treatment with a LTB4 antagonist did not reduce disease. We conclude that MRP-1 has an important role in the intestinal epithelial resistance to exogenous injury, but MRP-1 does not affect T-lymphocyte mediated mucosal damag

Cyclooxygenase-2 expression during carcinogenesis in the human stomach

The prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with a reduced risk of gastric cancer. The best-known target of these drugs is cyclooxygenase (COX); the COX-2 isoform is frequently up-regulated in gastric adenocarcinomas. Using the post-gastrectomy stomach as a model, the expression of COX-2 mRNA and protein has been investigated during tumour progression in the human stomach. COX-2 expression was comparable in gastric stump carcinomas and conventional gastric carcinomas and localized primarily to the cytoplasm of the neoplastic cells. COX-2 mRNA was elevated in biopsies containing intestinal metaplasia, as determined by reverse transcriptase polymerase chain reaction (RT-PCR). COX-2 immunopositivity became more frequent during progression from reactive epithelium to high-grade dysplasia, both in the epithelial and in the stromal cell compartment. Co-localization of COX-2 positive stromal cells was seen with CD68, alpha-smooth muscle actin (alpha-SMA), vimentin, and HLA-DR, but an as yet unidentified subpopulation of stromal cells remained. Co-localization with the macrophage marker CD68 was only observed in a minority of COX-2-positive cells. These data show that COX-2 expression is a relatively early event during carcinogenesis in the stomach. COX-2 expression increases during tumour progression in the stomach, suggesting a role for COX-2 expression in gastric tumourigenesis. Copyright (C) 2001 John Wiley Sons, Lt