Experimental non-steroidal anti-inflammatory drug-induced enteropathy in the rat: Similarities to inflammatory bowel disease and effect of thromboxane synthetase inhibitors

Abstract

We have validated an established animal model of acute inflammatory bowel disease in indomethacin-treated rats. Studies in both in vitro and in vivo 51chromium-labelled ethylenediamine tetra-acetate (51Cr-EDTA) permeability and tissue myeloperoxidase activity, a marker of inflammatory cell invasion, showed increased permeability and enzyme levels, respectively, in treated animals compared to controls (in vitro 51Cr-EDTA permeability: (mean (SE)) control 0.10 (0.02) μl/mg per tissue, experimental 0.17 (0.02) (p<0.01, 2 way analysis of variance); in vivo 51Cr-EDTA permeability: control 3.9 (1.3) (% dose recovered), experimental 12.1 (1.5) (p<0.01); tissue myeloperoxidase: control 10.8 (0.4) mU/mg, experimental 17.2 (0.5) (p<0.01). Pretreatment or simultaneous treatment of indomethacin-treated animals with glucocorticoids, sulphasalazine, or tetracycline reduced the permeability changes and the tissue inflammatory response (in vitro 51Cr-EDTA permeability: (mean (SE)) sulphasalazine+indomethacin 0.11 (0.2) μl/mg tissue (p<0.01), prednisolone±indomethacin 0.12 (0.02) (p<0.01), tetracycline+indomethacin 0.12 (0.02) (p<0.01)). Glucocorticoids and sulphasalazine, but not tetracycline, administered after the indomethacin also partially corrected the permeability and inflammatory changes induced by indomethacin (in vitro 51Cr-EDTA permeability: sulphasalazine 0.15 (0.02) μl/mg, p<0.02; prednisolone 0.12 (0.02) μl/mg, p<0.01)). This approach was used to investigate the effects of two different thromboxane synthetase inhibitors in indomethacin-treated animals. Simultaneous treatment with thromboxane synthetase inhibitors and indomethacin prevented the 51Cr-EDTA permeability and tissue myeloperoxidase increases induced by indomethacin alone (in vitro 51Cr-EDTA permeability: thromboxane synthetase inhibitors+indomethacin 0.11 (0.01) μl/mg (p<0.01); tissue myeloperoxidase: 11 (0.4) mU/mg, (p<0.01)). Thromboxane synthetase inhibitors administered after the indomethacin also partially corrected the permeability and inflammatory changes induced by indomethacin (in vitro 51Cr-EDTA permeability: thromboxane synthetase inhibitors 0.12 (0.02) mU/mg (p<0.01); tissue myeloperoxidase 13.8 (0.5) (p<0.01)). These studies indicate that thromboxane synthetase inhibitors partially correct the intestinal lesion non-steroidal anti-inflammatory drug enteropathy, and may therefore be of use in inflammatory bowel diseases in humans.