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Am J Physiol Cell Physiol 295: C800-C806, 2008. First published July 30, 2008; doi:10.1152/ajpcell.00157.2008
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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Aspirin induces gastric epithelial barrier dysfunction by activating p38 MAPK via claudin-7

Tadayuki Oshima,1,2 Hiroto Miwa,2 and Takashi Joh1

1Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Nagoya; and 2Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan

Submitted 17 March 2008 ; accepted in final form 22 July 2008

Tight junctions create a paracellular permeability barrier that is breached when nonsteroidal anti-inflammatory drugs cause gastrointestinal injury, including increased gastrointestinal permeability. However, the mechanism by which aspirin affects the function of gastric epithelial tight junctions is unknown. Thus, we examined the effect of aspirin on gastric mucosal barrier properties and tight junction organization using MKN28, a human gastric epithelial cell line that expresses claudin-3, claudin-4, claudin-7, zonula occludens (ZO)-1, and occludin, but not claudin-2 or claudin-5, as determined by immunoblot analysis and immunofluorescent staining. Aspirin (5 mM) treatment of MKN28 gastric epithelial monolayers significantly decreased transepithelial electrical resistance and increased dextran permeability. Both aspirin-mediated permeability and phosphorylation of p38 MAPK were significantly attenuated by SB-203580 (a p38 MAPK inhibitor) but not by U-0126 (a MEK1 inhibitor) or SP-600125 (a JNK inhibitor). Aspirin significantly decreased the quantity of claudin-7 protein produced by MKN28 cells but not the quantity of claudin-3, claudin-4, ZO-1, or occludin. The aspirin-induced decrease in claudin-7 protein was completely abolished by SB-203580 pretreatment. These results demonstrate, for the first time, that claudin-7 protein is important in aspirin-induced gastric barrier loss and that p38 MAPK activity mediates this epithelial barrier dysfunction.

tight junction; p38 mitogen-activated protein kinase; permeability


Address for reprint requests and other correspondence: T. Oshima, Div. of Upper Gastroenterology, Dept. of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan (e-mail: t-oshima{at}hyo-med.ac.jp)






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