Experimental non-steroidal anti-inflammatory drug-induced enteropathy in the rat: similarities to inflammatory bowel disease and effect of thromboxane synthetase inhibitors.
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) microliter/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 less than 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) microliter/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) microliter/mg, p < 0.02; prednisolone 0.12 (0.02) microliter/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) microliter/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 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.
Banerjee
A K
AK
Department of Clinical Biochemistry, King's College Hospital, London.
Peters
T J
TJ
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D002860:Chromium Radioisotopes / Q000378:metabolism; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000378:metabolism; D007082:Ileum / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000633:toxicity*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced*; D007583:Jejunum / Q000378:metabolism; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D011239:Prednisolone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012460:Sulfasalazine / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D002860:Chromium Radioisotopes; D007093:Imidazoles; C039242:dazmegrel; D012460:Sulfasalazine; D004492:Edetic Acid; D011239:Prednisolone; D009195:Peroxidase; D013930:Thromboxane-A Synthase; D013752:Tetracycline; D007213:Indomethacin