{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:44:50Z","timestamp":1791902690462,"version":"4.3.4"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2009,2,10]],"date-time":"2009-02-10T00:00:00Z","timestamp":1234224000000},"content-version":"vor","delay-in-days":3999,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[1998,3]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>In the stomach, prostaglandins protect the gastric mucosa against injuries. One rate\u2010limiting step in prostaglandin synthesis is mediated by prostaglandin endoperoxide synthase (PGHS), the target enzyme of non\u2010steroidal anti\u2010inflammatory drugs (NSAIDs). Two isoforms of PGHS exist: a constitutive (PGHS\u20101) and an inducible (PGHS\u20102) enzyme. PGHS\u20101 is the major source of gastric prostaglandins under physiological conditions. Inhibition of prostaglandin synthesis by traditional NSAIDs such as indomethacin and diclofenac which non\u2010selectively inhibit both PGHS\u20101 and PGHS\u20102, causes gastric and intestinal ulceration and delays gastric ulcer healing in chronic models. It has been shown that selective PGHS\u20102 inhibitors such as <jats:sc>L<\/jats:sc>\u2010745,337 (5\u2010methanesulphonamide\u20106\u2010(2,4\u2010difluorothio\u2010phenyl)\u20101\u2010indanone) are not ulcerogenic and do not inhibit gastro\u2010intestinal prostaglandin synthesis. However, minimal information is available on the long\u2010term effects of PGHS\u20102 inhibitors on the healing of previously established gastric injuries. We assessed the cellular localization and expression of PGHS\u20101 and PGHS\u20102 during gastric ulcer healing and assessed the effects of <jats:sc>L<\/jats:sc>\u2010745,337 on previously established cryoulcers in the rat gastric stomach.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>PGHS\u20101 and PGHS\u20102 were located and quantified by immunohistochemistry during experimental gastric ulcer healing. PGHS\u20102 immunoreactivity was only negligible in the normal gastric wall, but after gastric ulcerations, it was strongly detected in monocytes, macrophages, fibroblasts and endothelial cells below and between the regenerative glands. PGHS\u20101 immunoreactivity detected in normal gastric mucosa, disappeared after gastric ulceration in the mucosa adjacent to the ulcer crater. However, it reappeared in the regenerative glands from day 5 onwards. Thus, PGHS\u20101 and PGHS\u20102 were located at different sites and their maximal expression followed a different time\u2010sequence.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We assessed the effects of <jats:sc>L<\/jats:sc>\u2010745,337, indomethacin and diclofenac on gastric ulcer healing and histological healing parameters in rats. <jats:sc>L<\/jats:sc>\u2010745,337, indomethacin and diclofenac dose\u2010dependently decreased the healing of gastric ulcers. <jats:sc>L<\/jats:sc>\u2010745,337, indomethacin and diclofenac decreased epithelial cell proliferation in the ulcer margin and microvessel density in the ulcer bed on day 8 and increased the thickness of the granulation tissue below the ulcer crater and the gap between both edges of the muscularis mucosae on day 15. Indomethacin and diclofenac, but not <jats:sc>L<\/jats:sc>\u2010745,337, decreased synthesis of 6\u2010keto\u2010PGF<jats:sub>1\u03b1<\/jats:sub> and PGE<jats:sub>2<\/jats:sub> in tissue fragments from the stomach and terminal ileum and decreased platelet thromboxane B<jats:sub>2<\/jats:sub> synthesis in clotting whole blood.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Dose\u2010response curves for the inhibition of chronic gastric ulcer healing by <jats:sc>L<\/jats:sc>\u2010745,337 (administered twice daily intragastrically) showed an ID<jats:sub>50<\/jats:sub> value of 1.7\u2003mg (4.3\u2003\u03bcmol)\u2003kg<jats:sup>\u22121<\/jats:sup>. Dose\u2010response curves for the inhibition of PGE2 synthesis in inflammatory exudates in the acute carrageenin sponge rat model, showed ID50 values of 1.1\u2003\u2003mg (3.1\u2003\u2003\u03bcmol) kg<jats:sup>\u22121<\/jats:sup> and 1.3 (3.3\u2003\u2003\u03bcmol) mg kg\u22121 for indomethacin and <jats:sc>L<\/jats:sc>\u2010745,337, respectively. Thus, inhibition of chronic gastric ulcer healing by <jats:sc>L<\/jats:sc>\u2010745,337 occurs within a potentially therapeutic dose\u2010range.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In summary, PGHS\u20102 is markedly accumulated after gastric ulceration in monocytes, macrophages, fibroblasts and endothelial cells in regions of maximal repair activity. Selective inhibition of PGHS\u20102 by <jats:sc>L<\/jats:sc>\u2010745,337 delayed gastric ulcer healing though interference with epithelial cell proliferation, angiogenesis and maturation of granulation tissue in a potentially therapeutic dose range. PGHS\u20102\u2010derived prostaglandins seem to have an important role in gastric ulcer healing.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (1998) <jats:bold>123<\/jats:bold>, 795\u2013804; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0701672\">10.1038\/sj.bjp.0701672<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0701672","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T19:24:26Z","timestamp":1106940266000},"page":"795-804","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":228,"title":["Effects of inhibition of prostaglandin endoperoxide synthase\u20102 in chronic gastro\u2010intestinal ulcer models in rats"],"prefix":"10.1111","volume":"123","author":[{"given":"Adrian","family":"Schmassmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitta M.","family":"Peskar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Stettler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Netzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Stroff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Flogerzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Halter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,2,10]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119385"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02010727"},{"key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1016\/0016-5085(93)90667-2","article-title":"Side effects of nonsteroidal anti\u2010inflammatory drugs on the small and large intestine in humans","volume":"103","author":"Bjarnason I.","year":"1993","journal-title":"Gastroenterology"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0028-3908(94)90137-6"},{"key":"e_1_2_6_6_1","first-page":"1531","article-title":"Pharmacology of a selective cyclooxygenase\u20102 inhibitor, L\u2010745,337: A novel nonsteroidal anti\u2010inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach","volume":"274","author":"Chan C.\u2010C.","year":"1995","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2036.1997.154330000.x"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(97)70095-7"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-199110000-00006"},{"key":"e_1_2_6_10_1","doi-asserted-by":"crossref","first-page":"16737","DOI":"10.1016\/S0021-9258(17)44821-6","article-title":"The induction and expression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes","volume":"265","author":"Fu J.Y.","year":"1990","journal-title":"J. Biol. Chem."},{"key":"e_1_2_6_11_1","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/0016-5085(91)70012-M","article-title":"Effect of indomethacin on gastric mucosal blood flow around acetic induced gastric ulcers in rats","volume":"100","author":"Hirose H.","year":"1991","journal-title":"Gastroenterology"},{"issue":"3","key":"e_1_2_6_12_1","first-page":"A190","article-title":"Increased human gastric endothelial cell Cox\u20102 expression during angiogenesis","volume":"39","author":"Hull M.A.","year":"1996","journal-title":"Cut"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00398975"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/23.1.61"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1996.v111.pm8690211"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(93)90345-D"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)35698-9"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(90)92341-E"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00025a007"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(90)90340-7"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1997.v112.pm9024292"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1254\/jjp.61.123"},{"key":"e_1_2_6_23_1","first-page":"156","article-title":"Expression of mRNA for cyclooxygenase\u20101 and cyclooxygenase\u20102 in human tissues","volume":"350","author":"O'Neill G.P.","year":"1993","journal-title":"FEBS Lett."},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1995.tb15091.x"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01986569"},{"key":"e_1_2_6_26_1","doi-asserted-by":"crossref","first-page":"15473","DOI":"10.1016\/S0021-9258(17)40703-4","article-title":"Ligand\u2010induced prostaglandin synthesis requires expression of the Tis10\/PGS\u20102 prostaglandin synthase gene in murine fibroblasts and macrophages","volume":"269","author":"Reddy S.T.","year":"1994","journal-title":"J. Biol. Chem."},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119013"},{"key":"e_1_2_6_28_1","first-page":"433","article-title":"Cyto\u2010protection by prostaglandins in rat. Prevention of gastric necrosis produced by alcohol, Hcl, hypertonic NaCl, and thermal injury","volume":"77","author":"Robert A.","year":"1979","journal-title":"Gastroenterology"},{"key":"e_1_2_6_29_1","volume-title":"Angewandte Statistik","author":"Sachs L.","year":"1973"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(97)70005-2"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.35.7.896"},{"key":"e_1_2_6_32_1","first-page":"G276","article-title":"Influence of acid and angiogenesis on kinetics of gastric ulcer healing in rats: interaction with indomethacin","volume":"268","author":"Schmassmann A.","year":"1995","journal-title":"Am. J. Physiol."},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1990.tb03613.x"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119080"},{"issue":"1","key":"e_1_2_6_35_1","first-page":"S93","article-title":"Cellular mechanisms, interactions, and dynamics of gastric ulcer healing","volume":"21","author":"Tarnawski A.","year":"1995","journal-title":"J. Clin. Gastroenterol."},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/newbio231232a0"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/367215a0"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.6.2046"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1997.v112.pm9041264"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(82)90014-2"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.7.2692"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0701672","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0701672","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1038\/sj.bjp.0701672","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,28]],"date-time":"2023-10-28T00:52:08Z","timestamp":1698454328000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1038\/sj.bjp.0701672"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,3]]},"references-count":40,"journal-issue":{"issue":"5","published-print":{"date-parts":[[1998,3]]}},"alternative-id":["10.1038\/sj.bjp.0701672"],"URL":"https:\/\/doi.org\/10.1038\/sj.bjp.0701672","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,3]]},"assertion":[{"value":"2009-02-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}