UMLS:C0038358 - FACTA Search

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Query: UMLS:C0038358 (gastric ulcer)
5,179 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase (COX) is the enzyme that catalyzes the conversion of arachidonic acid to prostaglandin endoperoxides. In addition to constitutive COX-1, inducible COX-2 has been discovered. COX-2 is induced not only in acute exudative rat carrageenin-induced pleurisy, but in granuloma formation/proliferative inflammation for the acceleration of angiogenesis. This means that COX-2 is induced in the healing process of wounds such as in granuloma of gastric ulcer and the proliferative stage of endometrium. COX-2 is also introduced in ovulation and parturition. Osteoblasts induce COX-2 to accelerate bone absorption. Induction of COX-2 in colon carcinoma is a recent, very exciting topic of investigation. We can learn about many unknown roles of COX-2 from its knockout mouse, but the results must be interpreted cautiously. Development of selective COX-2 inhibitors, such as NS-398, opened a new era in which the side effects of gastric and renal lesions by NSAIDs could be ignored. However, prolongation of would healing by the inhibitors and transient expression of COX-2 must be considered in medical intervention with selective COX-2 inhibitors. Nevertheless, acute exudative inflammation, granuloma formation and bone absorption in rheumatoid arthritis are good targets for these inhibitors and application of these inhibitors will be extended to dysmenorrhea, interruption of abortion and increasing survival rate of patients with colon carcinoma.
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PMID:[Multiple roles of inducible cyclooxygenase-2 and its selective inhibitors]. 925 72

Recently, the state of cyclooxygenase (COX) mRNA expression has been reported in an acetic acid-induced chronic gastric ulcer model of mice. However, the time course of COX expression during the developmental stage and the subsequent repair process of acute gastric injury is not well understood at present. In this study, we quantitatively investigated the time course of the level of COX-2 and -1 mRNA expression from the developmental stage through the healing stage in ischemia-reperfusion (I-R)-induced acute gastric damage. COX-2 mRNA was expressed at low or undetectable levels in the normal gastric tissues of control rats. The COX-2 expression between 6 and 48 h following I-R was higher than that of the control gastric tissues; the histological findings were erosion during 1-36 h and transitional appearance from erosion to ulcer at 48 h. The maximum expression of COX-2 mRNA was recorded at 24 h (approximately 200-fold elevation). The COX-2 message was very low or undetectable at 72 h (ulcer stage) and at 96 and 120 h (healing stage of ulcer) after I-R. The level of COX-1 mRNA remained stable through all stages of acute gastric damage. These results are potentially useful for understanding the role of COX and evaluating the effects of drugs on expression of COX at various stages of acute gastric injury.
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PMID:Levels of cyclooxygenase-1 and -2 mRNA expression at various stages of acute gastric injury induced by ischemia-reperfusion in rats. 952 28

1. In the stomach, prostaglandins protect the gastric mucosa against injuries. One rate-limiting step in prostaglandin synthesis is mediated by prostaglandin endoperoxide synthase (PGHS), the target enzyme of non-steroidal anti-inflammatory drugs (NSAIDs). Two isoforms of PGHS exist: a constitutive (PGHS-1) and an inducible (PGHS-2) enzyme. PGHS-1 is the major source of gastric prostaglandins under physiological conditions. Inhibition of prostaglandin synthesis by traditional NSAIDs such as indomethacin and diclofenac which non-selectively inhibit both PGHS-1 and PGHS-2, causes gastric and intestinal ulceration and delays gastric ulcer healing in chronic models. It has been shown that selective PGHS-2 inhibitors such as L-745,337 (5-methanesulphonamide-6-(2,4-difluorothio-phenyl)-1-inda none) are not ulcerogenic and do not inhibit gastro-intestinal prostaglandin synthesis. However, minimal information is available on the long-term effects of PGHS-2 inhibitors on the healing of previously established gastric injuries. We assessed the cellular localization and expression of PGHS-1 and PGHS-2 during gastric ulcer healing and assessed the effects of L-745,337 on previously established cryoulcers in the rat gastric stomach. 2. PGHS-1 and PGHS-2 were located and quantified by immunohistochemistry during experimental gastric ulcer healing. PGHS-2 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-1 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-1 and PGHS-2 were located at different sites and their maximal expression followed a different time-sequence. 3. We assessed the effects of L-745,337, indomethacin and diclofenac on gastric ulcer healing and histological healing parameters in rats. L-745,337, indomethacin and diclofenac dose-dependently decreased the healing of gastric ulcers. L-745,337, 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 L-745,337, decreased synthesis of 6-keto-PGF1alpha and PGE2 in tissue fragments from the stomach and terminal ileum and decreased platelet thromboxane B2 synthesis in clotting whole blood. 4. Dose-response curves for the inhibition of chronic gastric ulcer healing by L-745,337 (administered twice daily intragastrically) showed an ID50 value of 1.7 mg (4.3 micromol) kg(-1). Dose-response curves for the inhibition of PGE2 synthesis in inflammatory exudates in the acute carrageenin sponge rat model, showed ID50 values of 1.1 mg (3.1 micromol) kg(-1) and 1.3 (3.3 micromol) mg kg(-1) for indomethacin and L-745,337, respectively. Thus, inhibition of chronic gastric ulcer healing by L-745,337 occurs within a potentially therapeutic dose-range. 5. In summary, PGHS-2 is markedly accumulated after gastric ulceration in monocytes, macrophages, fibroblasts and endothelial cells in regions of maximal repair activity. Selective inhibition of PGHS-2 by L-745,337 delayed gastric ulcer healing though interference with epithelial cell proliferation, angiogenesis and maturation of granulation tissue in a potentially therapeutic dose range. PGHS-2-derived prostaglandins seem to have an important role in gastric ulcer healing.
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PMID:Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. 953 6

Ulceration of the gastroduodenal mucosa occurs frequently in humans, particularly in patients with a history of peptic ulcer disease. In order for healing to occur, mucosal damage stimulates secretion of growth factors in the adjacent mucosa and ulcer bed. Peptic ulcer healing is accomplished by the filling of the mucosal defect with cells that migrate from the ulcer margin and by connective tissue, including microvessels originating from granulation tissue. Peptic ulcer healing is accelerated both in humans and experimental models by gastric acid inhibition, which enhances cell migration and maturation of the granulation tissue. In experimental models, peptic ulcer healing can also be accelerated by oral administration of basic fibroblast growth factor, which increases angiogenesis in the ulcer bed, or by nitric oxide-releasing compounds, which improve gastric blood flow. Clinical and experimental data indicate that traditional nonsteroidal anti-inflammatory drugs (NSAIDs) delay the healing of peptic ulcers by interfering with the action of growth factors, decreasing epithelial cell proliferation in the ulcer margin, decreasing angiogenesis in the ulcer bed, and slowing maturation of the granulation tissue. In order to reduce the gastroduodenal side-effects of NSAIDs, selective cyclo-oxygenase (COX)-2 inhibitors have been developed, which inhibit the inducible COX-2 isoform in inflammatory tissue but have only limited effect on the constitutive COX-1 isoform in the stomach. It has been reported that the selective COX-2 inhibitor L-745,337 has a reduced liability for gastrointestinal ulceration. In our chronic experimental gastric ulcer model in rats, however, delay of gastric ulcer healing with L-745,337 was comparable to that with ordinary NSAIDs. It has also been reported that nitric oxide-releasing NSAIDs have a low relative risk of gastrointestinal ulceration but, again, in our chronic gastric ulcer model, nitric oxide did not reverse NSAID-induced deleterious effects on ulcer healing. In contrast, the proton pump inhibitor omeprazole has been shown to reverse NSAID-induced deleterious effects on gastric ulcer healing in our model. Comparable results have also been reported in humans. Histologic analysis has shown that omeprazole reverses the effects of NSAIDs on cell proliferation, angiogenesis, and maturation of the granulation tissue. In conclusion, only highly effective gastric acid inhibition reliably reverses NSAID-induced delay of gastric ulcer healing.
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PMID:Mechanisms of ulcer healing and effects of nonsteroidal anti-inflammatory drugs. 957 20

Nonsteroidal anti-inflammatory drugs often cause development of significant GI lesions. Selective inhibitors of prostaglandin G/H synthase/cyclooxygenase-2 (PGHS-2) enzyme and some dual inhibitors of PGHS/5-lipoxygenase (5-LO) enzymes have been reported to be potent anti-inflammatory compounds that carry a much lower risk of having GI irritating effects. We have evaluated the anti-inflammatory effect and the GI safety profile of three new anti-inflammatory compounds: the selective PGHS-2 inhibitors NS-398 and PD 138387 and the PGHS/5-LO dual inhibitor PD 137968. All the compounds tested showed an anti-inflammatory activity in the carragenan footpad edema test in rats. None of these compounds caused either gastric damage 4 h after p.o. administration of 100 mg/kg in rats or inhibition of PGE2 synthesis in the stomach. However, when administered p.o. at an effective anti-inflammatory dose to rats with pre-existing acetic acid-induced gastric ulcer, NS-398 caused a statistically significant delay of ulcer healing. No impairment of the ulcer healing was observed with the other compounds evaluated. Derivatives of 2,6-di-tert-butylphenol, whose members may act as PGHS-1/PGHS-2 inhibitors, selective PGHS-2 inhibitors or PGHS/5-LO dual inhibitors, are novel anti-inflammatory compounds that are devoid of GI irritating effects and do not affect the rate of pre-existing gastric ulcer healing.
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PMID:Effects of novel anti-inflammatory compounds on healing of acetic acid-induced gastric ulcer in rats. 976 50

The efficacy and the adverse effects of non-steroid anti-inflammatory drugs (NSAIDs) are related mostly to inhibition of cyclo-oxygenase (COX), the main enzyme in prostaglandin synthesis. There are two isoenzymes: COX-1, mostly involved in the production of prostaglandins that are important for the normal function of the organism, such as protection of the stomach, vascular homeostasis and kidney function, and COX-2 which is induced by proinflammatory stimuli and is mostly present in inflammatory cells. Conceivably, the COX-1 and COX-2 functions are not separated very strictly. For instance, COX-2 may also come to expression as a reaction to physiological stimuli not connected with an inflammation. It is not yet clear how COX-2 selectivity can best be assessed. The degree of selectivity depends among other things on the test used and the time interval after which the activity is read. Because of the variable findings it is important to rank different NSAIDs on the basis of one and the same test. Use of NSAIDs that mostly inhibit COX-2 appears to result in reduction of the risk of gastric ulcer development. It is to be expected that the selective COX-2 inhibitors now being developed will make the use of NSAIDs even safer.
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PMID:[Non-steroidal anti-inflammatory agents (NSAID's) with lesser side effects by selective inhibition of cyclo-oxygenase-2]. 985 40

We investigated the role of endogenous interleukin (IL)-1 in the mRNA expression of cyclooxygenase (COX)-1, COX-2, inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant (CINC)-1, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and transforming growth factor (TGF)-beta1 in acetic acid-induced gastric ulcers in rats. IL-1beta mRNA was not detected in the normal or intact mucosa of ulcerated stomachs, but its expression was induced in the ulcerated tissue. IL-1beta immunoreactivity was observed in macrophages/monocytes and fibroblasts in the ulcer base. COX-2, iNOS, and CINC-1 mRNAs were expressed by ulceration. EGF, bFGF, HGF, and TGF-beta1 mRNA expression was detected in the normal mucosa, and their levels were significantly elevated by ulceration. In contrast, COX-1 mRNA level did not differ between the normal and ulcerated tissues. In a culture of isolated ulcer bases, block of IL-1 with IL-1 receptor antagonist (IL-1RA) dose-dependently and significantly reduced the mRNA levels of COX-2, iNOS, CINC-1, HGF, and bFGF. In contrast, COX-1, EGF, and TGF-beta1 mRNA expression was not affected by IL-1RA. IL-1RA dose-dependently reduced prostaglandin E(2) production, total and iNOS activities, neutrophil chemotactic activity, and growth-promoting activity toward gastric epithelial cells in the ulcer base. Finally, the administration of IL-1RA caused a significant impairment of ulcer healing. These results indicate that IL-1, expressed in macrophages/monocytes and fibroblasts in the ulcer base, might up-regulate the mRNA expression of COX-2, iNOS, CINC-1, HGF, and bFGF, thereby contributing to gastric ulcer healing in rats.
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PMID:Regulation by endogenous interleukin-1 of mRNA expression of healing-related factors in gastric ulcers in rats. 1052 82

Prostaglandins play a critical role in gastric mucosal cytoprotection and decrease progressively with age. Cyclooxygenase (COX), the rate-limiting enzyme for prostaglandin synthesis, exists in two isoforms, COX-1 and COX-2. The rat COX-1 gene expresses an alternatively spliced mRNA COX-1 splice variant (SV) that may, at best, code for a truncated COX-1 protein. With the use of competitive PCR, we determined whether COX gene expression was altered in the stomach with increasing age and after gastric ulcer induction. COX-1 mRNA was significantly reduced in the aged, and COX-1SV mRNA was significantly higher in the adults compared with the young and aged stomach. Levels of COX-1 and COX-2 were similarly expressed in the normal stomach. In acute gastric ulcers, only COX-2 mRNA levels were significantly elevated. When ulcers were undergoing healing and repair, COX-1 and COX-2 mRNA levels were significantly elevated. Age-related changes in COX-1 and COX-1SV but not COX-2 mRNA may alter gastric mucosal cytoprotection. Furthermore, COX-1 and COX-2 may both contribute to the healing of a gastric ulcer.
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PMID:Cyclooxygenase-1 and an alternatively spliced mRNA in the rat stomach: effects of aging and ulcers. 1080 Dec 75

In addition to housekeeping cyclooxygenase (COX)-1, which is constitutively expressed in many body cells, an inducible COX-2 has been described and cloned. Induction or presence of COX-2 has been reported not only in isolated cells, but also in cells in various tissues, as well as in both physiological and pathophysiological states, including acute exudative inflammation, proliferative inflammation, animal arthritis, rheumatoid arthritis, angiogenesis, bone absorption, gastric ulcer, colon cancer, hyperalgesia, Alzheimer's disease and certain states of the kidney, brain and female reproductive organs. This review article introduces results from recent works in these fields. COX-1- or COX-2-knockout mice may provide many clues on the roles of COX-2, but may simultaneously cause unnecessary confusion in the recognition of the roles of COX-2, and this is discussed. Recently the roles of COX-2 in exudative inflammation and the anti-inflammatory effects of selective COX-2 inhibitors have been questioned. This is discussed in the text. Prostanoids mediate signals to adjacent cells to provide fine regulation of cellular function. Because of the short duration of the expression of COX-2 gene and protein, COX-2 must play some roles different from those of COX-1 gene and protein in vivo. It is not yet possible to identify all the roles of COX-2, but in some tissues, such as the kidney, the brain and others, COX-2 may be expressed constitutively, whereas the prostaglandin generation by COX-2 may replace that by COX-1 in some states (or vice-versa). Precise analyses of the expression of COX-2 may disclose fine modulation of cellular and organ functions by PGs. Several selective or preferential COX-2 inhibitors have been developed and were shown to be effective in clinical trials. Most were reported to be free of adverse gastrointestinal effects, but it should be noted that in the healing process of gastric ulcers and in sodium-restricted states, adverse effects of selective COX-2 inhibitors could be expected. Soon, with more detailed knowledge of the delicate roles of COX-2 in vivo, effective and safe application of COX-2 inhibitors should be realized.
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PMID:Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors. 1102 54

Ulcer healing involves expression of various growth factors including hepatocyte growth factor (HGF) at the ulcer margin and the rise in plasma gastrin but the effects of locally applied HGF and gastrin, which are known to act as trophic factors for the gastric mucosa, with or without neutralizing antibodies against HGF and gastrin or COX-1 and COX-2 inhibitors on ulcer healing and the expression of cyclooxygenase (COX)-1 and COX-2 during this healing have been little studied. Rats with gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2) received a submucosal injection of either: 1)vehicle (saline), 2) HGF and 3) gastrin with or without neutralizing antibodies against HGF and gastrin or treatment with indomethacin (2 mg/kg-d i.p.), a non-specific inhibitor of COX, or NS-398 (5 mg/kg-d i.g.) and Vioxx (10 mg/kg-d i.g.), both highly specific COX-2 inhibitors. Each growth factor and specific antibodies against HGF and gastrin (100 ng/100 microl each) were injected just around the ulcer immediately after ulcer induction and this local application was repeated at day 2 following anesthesia and laparotomy. At day 13 and 21, the area of ulcers was determined by planimetry, the gastric blood flow (GBF) at ulcer margin was examined by H2-gas clearance technique and mucosal generation of PGE2 and the expression of COX-1 and COX-2 mRNA in the non-ulcerated and ulcerated gastric mucosa was analyzed using RT-PCR. The gastric ulcers healed progressively within 21 days and this effect was accompanied by significant increase in the GBF at the ulcer margin and expression of COX-2 mRNA and COX-2 protein at the ulcer area. Treatment with HGF and gastrin significantly accelerated the rate of ulcer healing and raised GBF at ulcer margin causing further significant upregulation of COX-2 mRNA and COX-2 protein (but not of COX-1 mRNA ) in the ulcerated mucosa. The upregulation of COX-2 mRNA induced by HGF was significantly attenuated by the concurrent local treatment with antibody against this growth peptide. Indomethacin and both COX-2 inhibitors significantly prolonged the ulcer healing, while suppressing the generation of PGE2 in non-ulcerated and ulcerated gastric mucosa and the GBF at ulcer margin. The acceleration of ulcer healing by HGF and gastrin and accompanying rise in the GBF at ulcer margin were significantly attenuated by the concurrent treatment with indomethacin or NS-398 and Vioxx. HGF injections produced a significant rise in the plasma gastrin levels and this was significantly attenuated by the cotreatment with NS-398. We conclude that 1) neutralization of HGF and gastrin by their specificantibodies delays ulcer healing due fall in the microcirculation around the ulcer and a decrease in the COX-2 expression, 2) COX-2 derived prostaglandins may play an important role in acceleration of the ulcer healing by various growth factors including HGF and gastrin, 3) enhancement of the local pool for growth factors such as HGF and gastrin at the ulcer site could offer a new modality for treatment of gastric ulcer.
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PMID:Involvement of cyclooxygenase (COX)-2 products in acceleration of ulcer healing by gastrin and hepatocyte growth factor. 1119 47

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