Abstract
Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1β in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.
Highlights
The recent widespread use of video capsule endoscopy and balloon-assisted enteroscopy revealed that non-steroidal anti-inflammatory drugs (NSAIDs) induce small-intestinal damage.[1,2,3,4] Our recent study showed that 25% of patients with rheumatoid arthritis who took non-steroidal antiinflammatory drug (NSAID) for more than 3 months had mild small-intestinal damage, and more important, 27.8% of patients had severe damage and decreased hemoglobin levels.[5]
Compared with the Standard diet (SD) group, in which mice were fed the SD we usually use in experimental studies on NSAID-induced small-intestinal damage, the lesion indices were markedly reduced in the gluten-free diet (GFD) group (Fig 1A and 1C)
We demonstrated that gliadin exacerbates NSAID-induced small-intestinal damage
Summary
The recent widespread use of video capsule endoscopy and balloon-assisted enteroscopy revealed that non-steroidal anti-inflammatory drugs (NSAIDs) induce small-intestinal damage.[1,2,3,4] Our recent study showed that 25% of patients with rheumatoid arthritis who took NSAIDs for more than 3 months had mild small-intestinal damage, and more important, 27.8% of patients had severe damage and decreased hemoglobin levels.[5]. In the pathophysiology of NSAID-induced small-intestinal damage, increase in mucosal permeability is one of the key mechanisms other than cyclooxygenase-mediated process.[8] In gastrointestinal tract, NSAIDs interact with phospholipids of cellular membrane and intracellular mitochondrial oxidative phosphorylation, which initiates biochemical changes that impair function of the mucosal barrier, which results in increase in intestinal permeability. Increased mucosal permeability induced by NSAIDs promotes recruitment of inflammationinducing molecules such as lipopolysaccharide (LPS)[9] and bile[10, 11] from the small-intestinal lumen to the mucosa and submucosa, and proinflammatory molecules stimulate immune cells, triggering inflammatory reactions.[8] In clinical studies, it was revealed that NSAID increases intestinal permeability in humans[12, 13]. Control of small-intestinal permeability could be the therapeutic and prophylactic target for NSAID-induced small-intestinal damage
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