Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2.

Reuter, Brian K.; Asfaha, Samuel; Buret, André G.; Sharkey, Keith A.; Wallace, John L.

doi:10.1172/jci119013

Cited by 402 publications

(303 citation statements)

References 44 publications

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“…45 Another study using COX-2-specific inhibitors in rodents with a chemically induced colitis showed exacerbation with colonic perforation after 1 week of treatment. 46 This rodent model of colitis may not be representative of human UC, however, because it is induced by trinitrobenzene sulfonic acid and yields a different histological picture than typical UC, making direct comparisons tenuous.…”

Section: Cox-2 Selective Inhibitor Therapy In Sporadic and Uc Neoplasiamentioning

confidence: 99%

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Agoff

Brentnall

Crispin

et al. 2000

The American Journal of Pathology

150

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Cyclooxygenase 2 (COX-2) overexpression has been described in sporadic colonic neoplasia, but its role in ulcerative colitis (UC) neoplastic progression remains unexplored. Although the specific role of cyclooxygenase in colonic neoplasia is uncertain, its inhibition by nonsteroidal anti-inflammatory drugs decreases the risk of sporadic colonic adenocarcinoma and causes regression of adenomas in familial adenomatous polyposis. To investigate the role of COX-2 in UC-associated neoplasia, we assessed COX-2 protein and mRNA expression throughout the spectrum of UC-associated neoplastic lesions in four total colectomy specimens, using immunocytochemistry and a novel TaqMan reverse transcriptase-polymerase chain reaction assay. The findings were correlated with DNA ploidy and inflammatory activity. We found COX-2 overexpression throughout the neoplastic spectrum in UC (P < 0.0001, R 2 ‫,)35.0؍‬ even in diploid samples that were negative for dysplasia. Overall, neoplastic change explained 53% of the variation in COX-2 expression, whereas inflammatory activity explained only 11%. COX-2 was overexpressed in all aneuploid samples and in 38% of diploid samples (P ‫؍‬ 0.0074). cDNA representational difference analysis was also performed and revealed that COX-2 mRNA was an up-regulated cDNA representational difference analysis difference product. COX-2 overexpression occurs early in UC-associated neoplasia, and the increase cannot be explained by inflammatory activity alone. The data suggest that COX-2-specific inhibitors may have a chemopreventative role in UC but the possibility that they could exacerbate UC inflammatory activity needs to be tested. Cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2) are cyclooxygenase enzymes that convert arachidonic acid to inflammatory and other physiological mediators, including prostaglandins, prostacyclin, and thromboxane. 1,2 COX-1 is constitutively expressed in most tissues, including the gastrointestinal tract, at a relatively stable level and is thought to help protect the gastrointestinal tract from injury. 1,2 COX-2 is an inducible cyclooxygenase whose production is stimulated by interleukin-1, tumor necrosis factor, and many other mediators. 1,2 COX-2 is thought to play a role in the reparative process after mucosal injury in the gastrointestinal tract. 1,2 Multiple studies suggest that COX-2 plays a role in sporadic colorectal neoplasia, based on its overexpression in colonic adenomas and carcinomas, as shown by both immunohistochemistry and reverse transcriptasepolymerase chain reaction (RT-PCR). [3][4][5] Cyclooxygenase inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) substantially decrease the risk of colorectal cancer, as well as the number and size of adenomas in familial adenomatous polyposis patients. 6 -8 Experimentally, NSAIDs prevent colonic adenocarcinoma in rodents with an familial adenomatous polyposis phenotype (the APC min mouse model). 9,10 Understanding the role of COX-2 in colonic neoplasia is thus particularly important because of these t...

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Section: Cox-2 Selective Inhibitor Therapy In Sporadic and Uc Neoplasiamentioning

confidence: 99%

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Agoff

Brentnall

Crispin

et al. 2000

The American Journal of Pathology

150

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“…Previous studies have demonstrated the speci®city of these antibodies. 6 Tissues were viewed with an epi¯uoresence microscope (Axioplan; Carl Zeiss Inc., Thornwood, NY) and photographed using TMax 400 ASA black and white ®lm (Eastman Kodak Co., Rochester, NY).…”

Section: Cox Immunohistochemistrymentioning

confidence: 99%

“…11±13 However, it has been suggested that, in situations in which the mucosa is in¯amed, COX-2 is likely to be expressed and produce prostaglandins that contribute to mucosal defence and ulcer healing. 2,6,7 For example, in an animal model of colitis, administration of selective inhibitors of COX-2 resulted in exacerbation of tissue injury, 6 while in a mouse model of gastric ulcer, administration of a selective COX-2 inhibitor delayed healing. 7 Little is known of the regulation of COX-2 expression within the gastrointestinal tract following acute injury.…”

Section: Introductionmentioning

confidence: 99%

Aspirin causes rapid up‐regulation of cyclo‐oxygenase‐2 expression in the stomach of rats

Davies

Sharkey

Asfaha

et al. 1997

Aliment Pharmacol Ther

125

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Background:Cyclo‐oxygenase‐1 (COX‐1) is believed to produce prostaglandins vital to mucosal defence, whereas cyclo‐oxygenase‐2 (COX‐2) is induced at sites of inflammation. Little is known about the regulation of COX‐2 in the stomach, particularly during the period following mucosal injury. In this study, we examined COX‐1 and COX‐2 expression shortly after administration of NSAIDs or ethanol.Methods:Fasted rats were given aspirin, salicylate, indomethacin or ethanol (20% or 40%) orally. Three hours later the stomach was excised, the severity of damage scored and samples taken for RT‐PCR of COX‐1 and COX‐2 mRNA and immunohistochemistry. Nitric oxide synthase mRNA (iNOS and eNOS) and activity were also measured.Results:Aspirin, indomethacin and the higher concentration of ethanol produced widespread mucosal damage, whereas salicylate and 20% ethanol caused only superficial epithelial damage. Aspirin caused a significant increase in COX‐2 mRNA expression and a marked increase in COX‐2 immunoreactivity, particularly in the superficial mucosa. Expression of COX‐1 (mRNA and protein) was unaffected by aspirin, as were NOS mRNA expression and enzyme activity. Pre‐treatment with prostaglandin E2 prevented the induction of COX‐2 by aspirin. Salicylate and indomethacin caused modest increases in COX‐2 immunoreactivity but no change in COX‐2 mRNA. Neither concentration of ethanol affected COX‐2 mRNA or protein expression, suggesting that this was a specific response to the aspirin, rather than to injury.Conclusions:These results demonstrate a rapid up‐regulation of COX‐2 expression in response to aspirin, possibly representing a compensatory response to inhibition of gastric prostaglandin synthesis.

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“…TNBS (100 mg/kg) in a vehicle of 50% ethanol (v/v) was instilled into the colon through the cannula. Following the instillation, the rats were held in a head-down position for 2 min to prevent the leakage of the intra-colonic instillation [26][27][28] . They were sacrificed 72 h after the colitis induction.…”

Section: Chemical Stimulation or Chemical Destruction Of Brain Nucleimentioning

confidence: 99%

“…The extent of macroscopic damage was assessed by a scoring system as described by Reuter et al [28] and Strober et al [29] with the following modifications: grade 0: no ulcer, no inflammation; grade 1: no ulcer, local hyperemia; grade 2: ulcer with no significant hyperemia and bowel wall thickening; grade 3: ulcer with one site of inflammation; grade 4: two or more sites of ulceration or inflammation; grade 5: major ulceration extending more than 1 cm along the length of the colon; grade 6-10: when the area of ulceration extended more than 2 cm along the colon, the score was increased by 1 for each additional cm of involvement. To assess the severity of diarrhea, the following criteria was used: grade 0: no diarrhea; grade 1: mild diarrhea; grade 2: severe diarrhea.…”

Section: Macroscopic Assessment Of Colonic Damage Score (Cds)mentioning

confidence: 99%

Glutamate microinjection into the hypothalamic paraventricular nucleus attenuates ulcerative colitis in rats

Zhang

Fei

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the effects of glutamate microinjection into hypothalamic paraventricular nucleus (PVN) on ulcerative colitis (UC) in rats and to explore the relevant mechanisms. Methods: 2,4,6-Trinitrobenzenesulfonic acid (100 mg/kg in 50% ethanol) was instilled into the colon of adult male SD rats to induce UC. A colonic damage score (CDS) was used to indicate the severity of the colonic mucosal damage. The pathological changes in the colonic mucosa were evaluated using immunohistochemistry, Western blotting, biochemical analyses or ELISA. Ten minutes before UC induction, drugs were microinjected into the relevant nuclei in rat brain to produce chemical stimulation or chemical lesion.Results: Microinjection of glutamate (3, 6 and 12 µg) into the PVN dose-dependently decreased the CDS in UC rats. This protective effect was eliminated after kainic acid (0.3 µg) was microinjected into PVN or into the nucleus tractus solitarius (NTS) that caused chemical lesion of these nuclei. This protective effect was also prevented when the AVP-V 1 receptor antagonist DPVDAV (200 ng) was microinjected into the NTS. The discharge frequency of the vagus was markedly decreased following microinjection of glutamate into the PVN. Microinjection of glutamate into the PVN in UC rats significantly increased the cell proliferation and anti-oxidant levels, and decreased the apoptosis and Bax and caspase 3 expression levels and reduced the pro-inflammatory factors in the colonic mucosa. Conclusion: The activation of hypothalamic PVN exerts protective effects against UC, which is mediated by the NTS and vagus. The effects may be achieved via anti-oxidative, anti-apoptotic, and anti-inflammatory factors.

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Exacerbation of inflammation-associated colonic injury in rat through inhibition of cyclooxygenase-2.

Cited by 402 publications

References 44 publications

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Aspirin causes rapid up‐regulation of cyclo‐oxygenase‐2 expression in the stomach of rats

Glutamate microinjection into the hypothalamic paraventricular nucleus attenuates ulcerative colitis in rats

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