Increase in tumor necrosis factor‐<i>α</i> production linked to the toxicity of indomethacin for the rat small intestine

Bertrand, Viviane; Guimbaud, Rosine; Tulliez, M; Mauprivez, Cédric; Sogni, Philippe; Couturier, Daniel; Giroud, Jean‐Paul; Chaussade, Stanislas; Chauvelot‐Moachon, Laurence

doi:10.1038/sj.bjp.0701968

Cited by 80 publications

(84 citation statements)

References 39 publications

(58 reference statements)

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“…In contrast, it has been reported that persistent and marked blockage of TNF-α bioactivity may have a detrimental effect on acute intestinal inflammation in a dextran sulfate sodium (DSS)-induced colitis model in mice (10). On the other hand, TNF-α is increased in indomethacin-induced intestinal ulcerations in rats and is involved at an early stage of NSAID toxicity in the small intestine (11). TNF-α may up-regulate other cytokines and pro-inflammatory mediators, and thereby cause tissue damage through the gradual rise in serum IL-1β and inducible nitric oxide synthase (iNOS)-derived NO levels (12).…”

Section: Introductionmentioning

confidence: 78%

“…Several lines of evidence support this hypothesis: (i) neutrophil depletion by intraperitoneal injection of anti-neutrophil antibody significantly attenuates the intestinal mucosal injury induced by indomethacin (13,16); (ii) intravital microscopic evaluation of the mesenteric circulation has shown that indomethacin promotes neutrophil adherence and emigration in post-capillary venules (23); and (iii) the induction of intestinal TNF-α production by NSAIDs was followed by activation of the neutrophil activation pathway (MPO activity) in the inflammation cascade, which could contribute to jejunum-ileum lesions (11). In this study, we have shown that MPO activity, an index of tissue-associated neutrophil accumulation, and the expression of KC mRNA, which is involved in chemotaxis and cell activation of neutrophils, were remarkably enhanced in the indomethacin-treated intestinal mucosa, and that these increases were significantly reduced in TNF-α -/-mice compared with WT mice.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that TNF-α may play a critical role in the pathogenesis of indomethacin-induced small intestinal injury (11,13,14). TNF-α is a pro-inflammatory cytokine capable of up-regulating its own expression as well as the expressions of other genes pivotal to the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

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Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Fukumoto

Naito

Takagi³

et al. 2011

Int J Mol Med

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Abstract. The pathogenesis of small intestinal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin is still unclear. For this reason, there is currently no therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF)-α exert beneficial effects on intestinal lesions in patients with inflammatory bowel disease (IBD). To clarify the participation of TNF-α in NSAID-induced small intestinal damage, we investigated the effects of indomethacin administration in mice with targeted deletion of the TNF-α gene. Indomethacin (10 mg/kg) was administered subcutaneously to male C57BL/6 (wild-type: WT) mice and TNF-α-deficient (TNF-α -/-) mice to induce small intestinal damage. The ulcer score, the tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration, and the expression of keratinocyte chemoattractant (KC) mRNA in the small intestinal mucosa were measured. In addition, we performed a TUNEL assay to evaluate indomethacininduced apoptosis of intestinal epithelial cells and measured the expression of caspase-3 protein and Bcl-2 mRNA. The ulcer score, MPO activity, and expression of KC mRNA were significantly increased after indomethacin administration. These increases were significantly inhibited in TNF-α -/-mice compared with WT mice. Apoptotic cells were observed by the TUNEL assay in the area of the ulcerative lesion, and they were significantly fewer in TNF-α -/-mice compared with WT mice. The expression of cleaved caspase-3 protein was induced by indomethacin administration, and significantly inhibited in TNF-α -/-mice compared with that of WT mice. The expression level of Bcl-2 mRNA in indomethacin-treated TNF-α -/-mice was significantly higher than that in WT mice. TNF-α plays an important role in the pathogenesis of indomethacin-induced small intestinal damage. These results suggest that TNF-α could become a new therapeutic target for NSAID-induced small intestinal damage.

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Section: Introductionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Fukumoto

Naito

Takagi³

et al. 2011

Int J Mol Med

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“…Indeed, TBARS and MPO activity in the small intestine were significantly increased after indomethacin treatment, and these responses were significantly inhibited by tacrolimus at the dose that prevented the development of intestinal lesions. On the other hand, Bertrand et al (27) demonstrated the involvement of TNF-α in the pathogenic mechanism of these lesions, especially in the early event preceding the elevation of NO production and MPO activity as well as lesion formation. TNF-α is known to induce the expression of iNOS in various cells including leukocytes (28,29).…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus (FK506), an Immunosuppressive Agent, Prevents Indomethacin-Induced Small Intestinal Ulceration in the Rat: Inhibition of Inducible Nitric Oxide Synthase Expression

Kato¹,

Nishio²,

Ogura³

et al. 2007

J Pharmacol Sci

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Abstract. We examined the effect of tacrolimus (FK506), an immunosuppressive drug, on indomethacin-induced small intestinal ulceration in rats. Animals were given indomethacin (10 mg / kg, s.c.), killed 24 h later, and myeloperoxidase (MPO) activity and thiobarbituric acid reactants (TBARS) were evaluated in intestinal lesions. Tacrolimus (0.3 -3 mg / kg) was administered p.o. twice 0.5 h before and 6 h after indomethacin injection. The expression of inducible nitric oxide synthase (iNOS) mRNA was determined by a TaqMan real-time RT-PCR, while the activity of nuclear factor (NF)-κB DNA-binding was analyzed by electrophoresis mobility shift assays (EMSA) 6 h after indomethacin treatment. Indomethacin provoked severe hemorrhagic lesions in the small intestine, mainly in the jejunum and ileum, accompanied with increases in MPO activity and TBARS. Oral administration of tacrolimus reduced the severity of indomethacin-induced intestinal lesions in a dose-dependent manner. The increases in MPO activity and TBARS were also significantly attenuated by tacrolimus. The expression of iNOS mRNA was markedly enhanced when examined 6 h after indomethacin administration, and this response was counteracted by tacrolimus. Indomethacin also activated NF-κB in a tacrolimus-preventable manner. These results suggest that tacrolimus prevents indomethacin-induced small intestinal ulceration in the rat. This effect may be due to inhibition of iNOS induction through suppression of NF-κB activation.

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“…The ceca from rofecoxib-and aspirin-treated animals were normal in appearance. Gross intestinal injury of indomethacin-treated rats has been well documented (Yamada et al, 1993;Bertrand et al, 1998), but not as thoroughly for ibuprofen. Histologically, either multifocal epithelial ulceration or inflammatory cell infiltrates were observed within the small intestine of ibuprofen-and indomethacintreated rats.…”

Section: Drug Signatures For the Acute Phase Responsementioning

confidence: 99%

NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression

Tugendreich

Pearson

Sagartz³

et al. 2006

Toxicol Pathol

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Toxicogenomics using a reference database can provide a better understanding and prediction of toxicity, largely by creating biomarkers that tie gene expression to actual pathology events. During the course of building a toxicogenomic database, an observation was made that a number of non-steroidal anti-inflammatory compounds (NSAIDs) at supra-pharmacologic doses induced an acute phase response (APR) and displayed hepatic gene expression patterns similar to that of intravenous lipopolysaccharide (LPS). Since NSAIDs are known to cause injury along the gastrointestinal tract, it has been suggested that NSAIDs increase intestinal permeability, allowing LPS and/or bacteria into the systemic circulation and stimulating an APR detectable in the liver. A short term study was subsequently conducted examining the effects of aspirin, indomethacin, ibuprofen, and rofecoxib to rats and a variety of endpoints were examined that included serum levels of inflammatory cytokines, histologic evaluation, and hepatic gene expression. Both indomethacin and ibuprofen injured the gastrointestinal tract, induced an APR, and increased serum levels of LPS, while rofecoxib and aspirin did not affect the GI tract or induce an APR. In treatments that eventually showed a systemic inflammatory response, hepatic expression of many inflammatory genes was noted as early as 6 hours after treatment well before alterations in traditional clinical pathology markers were detected. This finding led to the creation of a hepatic gene expression biomarker of APR that was effectively shown to be an early identifier of imminent inflammatory injury. In terms of the relative gastrointestinal safety and the NSAIDs studied, an important safety distinction can be made between the presumptive efficacious dose and the APR-inducing dose for indomethacin (1-2-fold), ibuprofen (5-fold), and rofecoxib (∼250-fold). Our data support the notion that NSAID-induced intestinal injury results in leakage of commensural bacteria and/or LPS into the circulation, provoking a systemic inflammatory response and that hepatic gene expression-based biomarkers can be used as early and sensitive biomarkers of APR onset.[The table referenced in this paper is not printed in this issue of Toxicologic Pathology. It is available as a downloadable text file in the online edition of Toxicologic Pathology, 34(2). In order to access the full article online, you must have either an individual subscription or a member subscription accessed through www.toxpath.org.]

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Increase in tumor necrosis factor‐α production linked to the toxicity of indomethacin for the rat small intestine

Cited by 80 publications

References 39 publications

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Tacrolimus (FK506), an Immunosuppressive Agent, Prevents Indomethacin-Induced Small Intestinal Ulceration in the Rat: Inhibition of Inducible Nitric Oxide Synthase Expression

NSAID-Induced Acute Phase Response is Due to Increased Intestinal Permeability and Characterized by Early and Consistent Alterations in Hepatic Gene Expression

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