Role of COX-2 in nonsteroidal anti-inflammatory drug enteropathy in rodents

Hotz-Behofsits, Christoph; Simpson, Robert J.; Walley, Matthew; Bjarnason, Ingvar

doi:10.3109/00365521003797205

Cited by 18 publications

(21 citation statements)

References 21 publications

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“…Although it has been stated that inhibition of both COX-1 and COX-2 is needed to induce small bowel injury (Takeuchi et al, 2010), the ability of etoricoxib to damage intestinal mucosa clearly shows that this is not the case. Moreover, studies in COX-1-and COX-2-deficient mice have suggested that the lack of COX-2 and the topical effect of NSAIDs (be they selective or not) lead to NSAID-enteropathy, without concomitant COX-1 inhibition (Hotz-Behofsits et al, 2010), and indeed, being devoid of topical irritancy, celecoxib was not enterotoxic, despite COX-2 inhibition.…”

Section: Discussionmentioning

confidence: 99%

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Fornai

Antonioli

Colucci

et al. 2013

J Pharmacol Exp Ther

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Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E 2 (PGE 2 ) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE 2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy.

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Section: Discussionmentioning

confidence: 99%

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Fornai

Antonioli

Colucci

et al. 2013

J Pharmacol Exp Ther

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“…Indomethacin has been widely used to model NSAID-induced enteropathy (9,16,19); yet despite extensive research, the exact mechanism whereby indomethacin disrupts the epithelial barrier remains a subject of debate. Indomethacin-induced gastrointestinal lesions have been linked to the suppression of prostaglandin production (16,43,47). This was widely accepted as the cause of NSAIDinduced enteropathy, and while there is little doubt that this is a major part of the problem, recent data implicate perturbed epithelial mitochondrial function (and oxidative stress due to ROS) (6,26) in indomethacin-induced gastropathy and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…NSAID use in humans (7,22) or administration to rodents (4,16,43) has been repeatedly shown to increase enteric epithelial permeability, and given the role that the epithelial barrier plays in holding the myriad of luminal antigens and microbes at bay (12,13,43), it is not surprising that NSAIDs can initiate or reactivate intestinal disease (5,28,39,42,51). Indomethacin has been widely used to model NSAID-induced enteropathy (9,16,19); yet despite extensive research, the exact mechanism whereby indomethacin disrupts the epithelial barrier remains a subject of debate. Indomethacin-induced gastrointestinal lesions have been linked to the suppression of prostaglandin production (16,43,47).…”

Section: Discussionmentioning

confidence: 99%

“…The exact mechanism behind the NSAIDinduced barrier dysfunction is not completely understood. The loss of cytoprotection due to NSAID-induced inhibition of cyclooxygenase (COX) activity and, hence, prostaglandin synthesis is certainly one component of NSAID-induced enteropathy (16,43,47). Studies have also linked indomethacininduced gastropathy to mitochondrial damage and dysfunction and, consequently, oxidative stress and apoptosis of gastric mucosal cells (19,26,43,45).…”

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confidence: 99%

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Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C

Schoultz

McKay

Graepel

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Schoultz I, McKay CM, Graepel R, Phan VC, Wang A, Söderholm J, McKay DM. Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C. Am J Physiol Gastrointest Liver Physiol 303: G536-G545, 2012. First published June 14, 2012 doi:10.1152/ajpgi.00125.2012.-The enteric epithelium must absorb nutrients and water and act as a barrier to the entry of luminal material into the body; this barrier function is a key component of innate immunity. Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy occurs via inhibition of prostaglandin synthesis and perturbed epithelial mitochondrial activity. Here, the direct effect of NSAIDs [indomethacin, piroxicam (cyclooxygenase 1 and 2 inhibitors), and SC-560 (a cyclooxygenase 1 inhibitor)] on the barrier function of human T84 epithelial cell line monolayers was assessed by transepithelial electrical resistance (TER) and internalization and translocation of a commensal Escherichia coli. Exposure to E. coli in the presence and absence of drugs for 16 h reduced TER; however, monolayers cotreated with E. coli and indomethacin, but not piroxicam or SC-560, displayed significant increases in internalization and translocation of the bacteria. This was accompanied by increased reactive oxygen species (ROS) production, which was also increased in epithelia treated with E. coli only. Colocalization revealed upregulation of superoxide synthesis by mitochondria in epithelia treated with E. coli ϩ indomethacin. Addition of antioxidants (vitamin C or a green tea polyphenol, epigallocathechin gallate) quenched the ROS and prevented the increase in E. coli internalization and translocation evoked by indomethacin, but not the drop in TER. Evidence of increased apoptosis was not observed in this model. The data implicate epithelial-derived ROS in indomethacin-induced barrier dysfunction and show that a portion of the bacteria likely cross the epithelium via a transcellular pathway. We speculate that addition of antioxidants as dietary supplements to NSAID treatment regimens would reduce the magnitude of decreased barrier function, specifically the transepithelial passage of bacteria. permeability; nonsteroidal anti-inflammatory drug; mitochondria; intestine

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“…PPI can significantly worsen NSAID-induced damage in the small intestine [5,16]. Intestinal damage occurs when both COX-1 and COX-2 are inhibited, especially COX-2 [17,18]. Nitric oxide derived by iNOS plays a key pathogenic role in the ulcerogenic process [19][20][21].…”

Section: Probable Mechanisms Of Non-steroidal Antiinflammatory Drug (mentioning

confidence: 99%

Non-Steroidal Anti-Inflammatory Drug (NSAID)-Induced Small Intestinal Injury

Tajima¹

2013

Pharm Anal Acta

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Role of COX-2 in nonsteroidal anti-inflammatory drug enteropathy in rodents

Cited by 18 publications

References 21 publications

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C

Non-Steroidal Anti-Inflammatory Drug (NSAID)-Induced Small Intestinal Injury

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