Nonsteroidal Anti-Inflammatory Drugs Activate Quiescent Inflammatory Bowel Disease

Kaufmann, Herbert J.; Taubin, Howard

doi:10.7326/0003-4819-107-4-513

Cited by 321 publications

(117 citation statements)

References 22 publications

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“…26 Our observation of enhanced production of PGD 2 via COX2 in IBD is consistent with prior literature (see Results). Wallace et al showed that normal colon expresses low levels of COX.…”

Section: Hatoum Et Al Novel Nonendothelial Release Of Pgd 2 2359supporting

confidence: 82%

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Novel Mechanism of Vasodilation in Inflammatory Bowel Disease

Hatoum

Gauthier

Binion

et al. 2005

ATVB

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Objective-Endothelium-dependent dilation to acetylcholine (Ach) is reduced in mucosal arterioles from patients with inflammatory bowel disease (IBD). The contributions of both nitric oxide (NO) and endothelial-derived hyperpolarizing factor (EDHF) are decreased. We hypothesized that the remaining dilation results from products of cyclooxygenase. Methods and Results-High-performance liquid chromatography (HPLC) was used to isolate eicosanoid vasodilator products and videomicroscopy was used to examine vasomotor responses in human mucosal arterioles from subjects with or without IBD undergoing bowel resection surgeries. In subjects without IBD, Ach constricted (Ϫ52%Ϯ10%) arterioles devoid of endothelium. Indomethacin (INDO) (cyclooxygenase inhibitor) had no effect. In contrast, Ach dose-dependently dilated both intact and endothelial denuded arterioles from patients with IBD. The dilation was converted to constriction by INDO (Ϫ54%Ϯ9%; PϽ0.05 versus non-IBD) or by BWA868C (PGD 2 receptor antagonist). Only in arterioles from subjects with IBD did Ach produce an arachidonic acid metabolite that comigrated on HPLC with PG D 2 (PGD 2 ). Exogenous PGD 2 dilated (maxϭ66%Ϯ4%) IBD arterioles. Conclusion-In arterioles from IBD patients, Ach-mediated dilation shifts from endothelial production of NO and EDHF to nonendothelial generation of a PG, likely PGD 2 . This is a novel dilator mechanism arising from nonendothelial vascular tissue that compensates for loss of endothelium-dependent dilation. PGD 2 appears to be important in regulating mucosal blood flow in patients with IBD, implicating potentially detrimental effects from nonsteroidal antiinflammatory drugs. Key Words: cyclooxygenase Ⅲ inflammatory bowel disease Ⅲ microcirculation Ⅲ prostaglandin Ⅲ vasodilation E ndothelium-dependent vasorelaxation plays a critical role in regulating tissue perfusion. 1 Impaired vasorelaxation is a key feature of microvascular dysfunction that contributes to the pathophysiology of diabetes mellitus, hyperlipidemia, and atherosclerosis. 2,3 A new association of microvascular dysfunction with clinical inflammatory bowel disease (IBD) (Crohn disease, ulcerative colitis) has been made. 4 IBD is characterized by refractory, poorly healing mucosal ulcerations, and impaired endothelium-mediated vasorelaxation. 4,5 Using in vitro dimension measurements of cannulated 50 to 200 m arterioles, we have demonstrated that normal intestinal microvessels dilate in response to the classic endothelium-dependent agonist, acetylcholine (Ach). 4 After inhibiting nitric oxide (NO) synthase, cyclooxygenase (COX), and hyperpolarization mechanisms, or after endothelial denudation, constriction was observed. Microvessels isolated from chronically inflamed IBD tissue demonstrated loss of NO-mediated and hyperpolarization-mediated vasodilation in response to Ach. However, in contrast to vessels from subjects without IBD or from uninvolved segments of bowel from patients with IBD, arterioles from active IBD segments had attenuated dilation to Ach that was independ...

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“…26 Our observation of enhanced production of PGD 2 via COX2 in IBD is consistent with prior literature (see Results). Wallace et al showed that normal colon expresses low levels of COX.…”

Section: Hatoum Et Al Novel Nonendothelial Release Of Pgd 2 2359supporting

confidence: 82%

“…These findings may also help explain the toxicity of NSAIDS in the treatment of IBD where their use results in the impairment of the sole remaining microvascular dilator mechanism to Ach, and presumably parasympathetic activation in the mucosa. 26 …”

Section: Hatoum Et Al Novel Nonendothelial Release Of Pgd 2 2359mentioning

confidence: 99%

Novel Mechanism of Vasodilation in Inflammatory Bowel Disease

Hatoum

Gauthier

Binion

et al. 2005

ATVB

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“…Caution is warranted, however, as COX-2 selective inhibition has been shown to impair healing of gastric ulcers in some studies, 43 and NSAID use may exacerbate the activity of idiopathic inflammatory bowel disease. 44 There are, however, few published data on NSAID exacerbation of idiopathic inflammatory bowel disease, either Crohn's disease or UC. A recent retrospective cohort study of 1,940 inflammatory bowel disease patients (881 had Crohn's disease and 1,059 had UC), followed for an average of 3.1 years, demonstrated that the majority of inflammatory bowel disease patients use NSAID analgesics, and that their use is not associated with disease flares, as analyzed by multivariate Cox proportional hazards models (hazard ratio, 0.93; 95% confidence interval, 0.68 to 1.27).…”

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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“…40,41 Based on our finding that PGE 2 induces ID1 in endothelial cells, it is possible that nonsteroidal anti-inflammatory drugs prevent the up-regulation of vascular ID1 in colitis, thereby leading to more severe disease. Loss of Id1 is shown here to enhance the frequency of CD31 þ aggregates, increase vessel leakiness, and enhance Hif-1a expression adjacent to the CD31 þ aggregates in experimental colitis.…”

Section: Discussionmentioning

confidence: 99%

Id1 Expression in Endothelial Cells of the Colon Is Required for Normal Response to Injury

Zhang

Subbaramaiah

Yantiss

et al. 2015

The American Journal of Pathology

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Inhibitor of DNA binding (ID)-1 is important for angiogenesis during embryogenesis and tumor development. Whether ID1 expression in endothelial cells of the colon is required for normal response to injury is unknown. We demonstrate that Id1 is up-regulated in colonic endothelial cells in an experimental model of colitis and in the inflamed mucosa of patients with inflammatory bowel disease. Because prostaglandin E 2 and tumor necrosis factor-a are also elevated in colitis, we determined whether these factors could induce ID1 transcription in cultured endothelial cells. Tumor necrosis factor-a stimulated ID1 transcription via early growth response 1 protein (Egr-1). By contrast, the induction of ID1 by prostaglandin E 2 was mediated by cAMP response elementebinding protein (CREB). To determine whether the increased ID1 levels in the endothelial cells of inflamed mucosa were an adaptive response that modulated the severity of tissue injury, Id1 was conditionally depleted in the endothelium of mice, which sensitized the mice to more severe chemical colitis, including more severe diarrhea, bleeding, and histological injury, and shorter colon compared with control mice. Moreover, depletion of Id1 in the vasculature was associated with increased CD31 þ aggregates and increased vascular permeability in inflamed mucosa compared with those in Id1 wild-type control mice. These results suggest that endothelial ID1 up-regulation in inflamed colonic mucosa is an adaptive response that modulates the severity of tissue injury. (Am J Pathol 2015 http://dx

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Nonsteroidal Anti-Inflammatory Drugs Activate Quiescent Inflammatory Bowel Disease

Cited by 321 publications

References 22 publications

Novel Mechanism of Vasodilation in Inflammatory Bowel Disease

Novel Mechanism of Vasodilation in Inflammatory Bowel Disease

The Role of Cyclooxygenase 2 in Ulcerative Colitis-Associated Neoplasia

Id1 Expression in Endothelial Cells of the Colon Is Required for Normal Response to Injury

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