We have validated an established animal model of acute inflammatory bowel disease in indomethacin-treated rats. Studies in both in vitro and in vivo chromium-51-labelled ethylenediamine tetra-acetate (Cr-51-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 Cr-51-EDTA permeability: (mean (SE)) control 0.10 (0.02)-mu-l/mg per tissue, experimental 0.17 (0.02) (p < 0.01, 2 way analysis of variance); in vivo Cr-51-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 CR-51-EDTA permeability: (mean (SE)) sulphasalazine+indomethacin 0.11 (0.2)-mu-l/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 Cr-51-EDTA permeability: sulphasalazine 0.15 (0.02)-mu-l/mg, p < 0.02; prednisolone 0.12 (0.02)-mu-l/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 Cr-51-EDTA permeability and tissue myeloperoxidase increases induced by indomethacin alone (in vitro Cr-51-EDTA permeability: thromboxane synthetase inhibitors+indomethacin 0.11 (0.1) mu-l/mg (p0.01); 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 Cr-51-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 nonsteroidal anti-inflammatory drug enteropathy, and may therefore be of use in inflammatory bowel diseases in humans.
