Role of cyclooxygenase-2 (Cox-2) in the healing of gastric ulcers in rats

Shigeta, Jun-ichi; Takahashi, Satoru; Itō, Makoto; Okabe, Susumu

doi:10.1016/s0016-5085(98)81160-8

Cited by 48 publications

(88 citation statements)

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“…However, indomethacin treatment did not affect the neutrophil migration induced by either IL-15 or N-formylmethionylleucyl-phenylalanine, a nonspecific flogistic stimulus (data not shown), indicating that prostanoids are specifically involved in IL-23-induced neutrophil migration. Notably the range of indomethacin dose that inhibited mBSA-or IL-23-induced neutrophil migration corresponds to the range that inhibits prostanoid production in vivo (23). IL-23 also triggered a significant increase in COX-2 mRNA expression in peritoneal cells 30 min after IL-23 injection.…”

Section: The Il-23/il-17 Axis Is Essential For the Neutrophil Migratimentioning

confidence: 71%

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

Lemos

Grespan

Vieira

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

122

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IL-23/IL-17-induced neutrophil recruitment plays a pivotal role in rheumatoid arthritis (RA). However, the mechanism of the neutrophil recruitment is obscure. Here we report that prostaglandin enhances the IL-23/IL-17-induced neutrophil migration in a murine model of RA by inhibiting IL-12 and IFN γ production. Methylated BSA (mBSA) and IL-23-induced neutrophil migration was inhibited by anti-IL-23 and anti-IL-17 antibodies, COX inhibitors, IL-12, or IFNγ but was enhanced by prostaglandin E 2 (PGE 2 ). IL-23-induced IL-17 production was increased by PGE 2 and suppressed by COX-inhibition or IL-12. Furthermore, COX inhibition failed to reduce IL-23-induced neutrophil migration in IL-12- or IFNγ-deficient mice. IL-17-induced neutrophil migration was not affected by COX inhibitors, IL-12, or IFNγ but was inhibited by MK886 (a leukotriene synthesis inhibitor), anti-TNFα, anti-CXCL1, and anti-CXCL5 antibodies and by repertaxin (a CXCR1/2 antagonist). These treatments all inhibited mBSA- or IL-23-induced neutrophil migration. IL-17 induced neutrophil chemotaxis through a CXC chemokines-dependent pathway. Our results suggest that prostaglandin plays an important role in IL-23-induced neutrophil migration in arthritis by enhancing IL-17 synthesis and by inhibiting IL-12 and IFNγ production. We thus provide a mechanism for the pathogenic role of the IL-23/IL-17 axis in RA and also suggest an additional mechanism of action for nonsteroidal anti-inflammatory drugs.

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Section: The Il-23/il-17 Axis Is Essential For the Neutrophil Migratimentioning

confidence: 71%

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

Lemos

Grespan

Vieira

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

122

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“…Moreover, COX-2 expression is markedly up-regulated in gastric ulcers and its inhibition results in a delay in ulcer healing processes (Perini et al 2003) as COX-2 enhances angiogenesis and induces growth factors responsible for ulcer repair (Mizuno et al 1997) through induction of the proliferation of epithelial cells during the repair process (Tarnawski 2005). Interestingly, COX-2 provides a ''back-up source'' for PG production when COX-1-induced PG synthesis is reduced (Shigeta et al 1998). This suggests that, along with COX-1, the activity of COX-2 serves as another defense mechanism key to maintenance of mucosal integrity and ulcer healing.…”

Section: Discussionmentioning

confidence: 99%

Serotonin and histamine mediate gastroprotective effect of fluoxetine against experimentally-induced ulcers in rats

Sokar

Elsayad

Ali

2016

Journal of Immunotoxicology

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Research in the treatment of gastric ulcer has involved the investigation of new alternatives, such as anti-depressant drugs. The present study was designed to investigate the gastroprotective effects of fluoxetine against indomethacin and alcohol induced gastric ulcers in rats and the potential mechanisms of that effect. Fluoxetine (20 mg/kg) was administered IP for 14 days. For comparative purposes, other rats were treated with ranitidine (30 mg/kg). Thereafter, after 24 h of fasting, INDO (100 mg/kg) or absolute alcohol (5 ml/kg) was administered to all rats (saline was administered to naïve controls) and rats in each group were sacrificed 5 h (for INDO rats) or 1 h (for alcohol rats) later. Macroscopic examination revealed that both fluoxetine and ranitidine decreased ulcer scores in variable ratios, which was supported by microscopic histopathological examination. Biochemical analysis of fluoxetine-or ranitidine-pre-treated host tissues demonstrated reductions in tumor necrosis factor (TNF)-and myeloperoxidase (MPO) levels and concomitant increases in gastric pH, nitric oxide (NO) and reduced glutathione (GSH) contents. Fluoxetine, more than ranitidine, also resulted in serotonin and histamine levels nearest to control values. Moreover, immuno-histochemical analysis showed that fluoxetine markedly enhanced expression of cyclooxygenases COX-1 and COX-2 in both models; in comparison, ranitidine did not affect COX-1 expression in either ulcer model but caused moderate increases in COX-2 expression in INDOinduced hosts and high expression in alcohol-induced hosts. The results here indicated fluoxetine exhibited better gastroprotective effects than ranitidine and this could be due to anti-secretory, anti-oxidant, anti-inflammatory and anti-histaminic effects of the drug, as well as a stabilization of gastric serotonin levels. ARTICLE HISTORY

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“…As expected, our PGE 2 regimen significantly increased bone formation and bone mass, but none of these effects was abrogated by COX-2 inhibition. NS-398 is known to preferentially inhibit COX-2 and the doses that were used are known to inhibit COX-2 activity in a variety of systems (Hirata et al 1997, Mikuni et al 1998, Shigeta et al 1998. In addition, the foot-pad edema model that we used proved that the dose and route of administration were effective in vivo.…”

Section: Figurementioning

confidence: 89%

“…All PGE 2 -injected rats received another injection, 45 min prior to PGE 2 : group 2 received 0·1 ml DMSO/rat, group 3 received a low dose (3 mg/kg) of NS-398 (Cayman Chemical, Ann Arbor, MI, USA) dissolved in 0·1 ml DMSO, and group 4 received a high dose (10 mg/kg) of NS-398. These doses were selected based on published papers (Hirata et al 1997, Mikuni et al 1998, Shigeta et al 1998. All rats were injected with calcein (Sigma, St Louis, MO, USA) at 15 mg/kg, 8 and 2 days prior to death to measure dynamic parameters of bone formation.…”

Section: In Vivo Anabolic Testingmentioning

confidence: 99%

Inhibition of cyclo-oxigenase-2 activity does not abolish the anabolic effect of prostaglandin E2 in vivo or in vitro

Weinreb

Kelner²,

Keila³

2002

Journal of Endocrinology

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It was previously reported that the expression of cyclooxigenase-2 (COX-2) is induced by prostaglandin E 2 (PGE 2 ) in vitro in an osteogenic cell line and organ culture, suggesting an autoamplification mechanism. In this study, we first tested whether this phenomenon also occurs in bone tissue in vivo and found that a single anabolic dose of PGE 2 (5 mg/kg) induced (between 30 and 120 min) in rat tibiae, an increase in the mRNA level of COX-2 (2·5-to 9-fold) but not that of COX-1. Secondly, to test whether COX-2 activity in generating endogenous prostaglandins (PGs) is required for the in vivo anabolic properties of PGE 2 , young male rats were injected daily with either vehicle (8% ethanol) or 5 mg/kg PGE 2 for 21 days. PGE 2 -injected rats received, 45 min prior to PGE 2 , either dimethyl sulphoxide (as vehicle) or one of two doses of NS-398, a selective COX-2 inhibitor: a low dose (3 mg/kg) or a high dose (10 mg/kg). PGE 2 increased bone formation (measured as cancellous mineralizing surface, mineral apposition rate and bone formation rate) and bone mass (measured as cancellous bone area and surface and cortical width). None of these increases was suppressed by pre-administration of NS-398. In contrast, the high dose of NS-398 effectively suppressed an increase in rat hind-paw volume induced by a local carrageenan injection. Furthermore, since COX-2 inactivation may affect PG receptor expression, we found that preadministration of NS-398 did not abolish the induction in EP 4 receptor mRNA levels, caused by PGE 2 in rat bone tissue. For in vitro testing, rat femoral bone marrow stromal cell cultures were initiated and were incubated in the absence or presence of PGE 2 at 100 nM (as an inducer) and with increasing concentrations of NS-398 (10 8 M to 10 5 M) for 21 days, after which time mineralized (Von-Kossa positive) nodules were counted. PGE 2 increased nodule formation as previously reported; however, NS-398 reduced nodule formation in both control and PGE 2 -treated cultures to the same extent. We conclude that while the level of COX-2 mRNA is increased in vivo by administration of PGE 2 , inhibition of its activity (i.e. generation of endogenous PGs) does not abolish the anabolic effect of PGE 2 .

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Role of cyclooxygenase-2 (Cox-2) in the healing of gastric ulcers in rats

Cited by 48 publications

References 0 publications

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

Serotonin and histamine mediate gastroprotective effect of fluoxetine against experimentally-induced ulcers in rats

Inhibition of cyclo-oxigenase-2 activity does not abolish the anabolic effect of prostaglandin E2 in vivo or in vitro

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