Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent

Watanabe, Toshio; Higuchi, Kazuhide; Kobata, Atsushi; Nishio, Hisahide; Tanigawa, Tetsuya; Shiba, Masatsugu; Tominaga, Kazunari; Fujiwara, Yasuhiro; Oshitani, Nobuhide; Asahara, Takashi; Nomoto, Koji; Takeuchi, Koji; Arakawa, Tetsuo

doi:10.1136/gut.2007.125963

Cited by 198 publications

(229 citation statements)

References 29 publications

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“…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: 60%

“…Several reports have demonstrated the increases in intestinal TNF-α mRNA expression in this model of small intestinal injury (13). Watanabe et al (13) demonstrated that the expression of TNF-α was increased in the small intestine after indomethacin treatment through a Toll-like receptor (TLR) 4-dependent pathway. Bertrand et al (11) also reported that TNF-α production was linked to the toxicity of indomethacin in the small intestine, especially at the early stage of the ulcerogenic process, and that the inhibition of TNF-α synthesis reduced indomethacin-induced intestinal injury in rats.…”

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%

“…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). Immunoneutralization of TNF-α or MCP-1, as well as neutrophil depletion, exerts a preventive effect on indomethacin-induced intestinal damage in rats (13,14). Thus, the role of TNF-α in the pathogenesis of acute intestinal inflammation is still controversial.…”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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“…It is well that NSAIDs do not induce small-bowel injury in germ-free animals [20]. Watanabe et al reported that lipopolysaccharides (LPS)/toll-like receptor 4 (TLR4)/ MyD88-dependent signaling pathway plays an important role in the development of such injuries [32]. Acid is closely involved in gastric mucosal injury.…”

Section: Present Status Of Small Intestinal Mucosal Injury Caused By mentioning

confidence: 99%

Present status and strategy of NSAIDs-induced small bowel injury

et al. 2009

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Non-steroidal anti-inflammatory drugs (NSAIDs) are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. The prevalence of NSAIDs-induced small intestinal injury is higher than had been expected. Recent studies show that more than 50% of patients taking NSAIDs have some mucosal damage in the small intestine. The gross appearance of NSAIDinduced enteropathy varies, appearing variously as diaphragm-like strictures, ulcers, erosions, and mucosal redness. To investigate NSAID-induced enteropathy, and to rule out other specific enteropathies, other useful methods (in addition to capsule endoscopy and balloon enteroscopy) include such modalities as radiological examination of the small intestine, the permeability test, scintigraphy or the fecal excretion test using 111 Indium-labeled white blood cells, and measurement of the fecal calprotectin concentration. Diaphragm-like strictures and bleeding from mucosal breaks may be treatable with interventional enteroscopy. Misoprostol, metronidazole, and sulfasalazine are frequently used to treat NSAID-induced enteropathy, but have undesirable effects in some cases. In the experimental model, we confirmed that several existing drugs for gastroduodenal ulcers prevented indomethacin-induced small intestinal injury. Such drugs may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine. We hope to examine these drugs in future clinical studies.

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Gastrointestinal Tract

2012

Comparative Pathophysiology and Toxicology of Cyclooxygenases

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Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent

Abstract: Indomethacin may injure the small intestine through a TLR4/MyD88-dependent pathway.

Cited by 198 publications

References 29 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

Present status and strategy of NSAIDs-induced small bowel injury

Gastrointestinal Tract

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