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Am J Physiol Gastrointest Liver Physiol 283: G122-G132, 2002. First published March 20, 2002; doi:10.1152/ajpgi.00015.2002
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Vol. 283, Issue 1, G122-G132, July 2002

Na+/H+ exchanger blockade inhibits enterocyte inflammatory response and protects against colitis

Zoltán H. Németh1, Edwin A. Deitch1, Csaba Szabó1,2, Jon G. Mabley2, Pál Pacher2, Zoltán Fekete1, Carl J. Hauser1, and György Haskó1

1 Department of Surgery, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103; and 2 Inotek Corporation, Beverly, Massachusetts 01915

Na+/H+ exchangers (NHEs) are integral transmembrane proteins found in all mammalian cells. There is substantial evidence indicating that NHEs regulate inflammatory processes. Because intestinal epithelial cells express a variety of NHEs, we tested the possibility that NHEs are also involved in regulation of the epithelial cell inflammatory response. In addition, since the epithelial inflammatory response is an important contributor to mucosal inflammation in inflammatory bowel disease (IBD), we examined the role of NHEs in the modulation of disease activity in a mouse model of IBD. In human gut epithelial cells, NHE inhibition using a variety of agents, including amiloride, 5-(N-methyl-N-isobutyl)amiloride, 5-(N-ethyl-N-isopropyl)- amiloride, harmaline, clonidine, and cimetidine, suppressed interleukin-8 (IL-8) production. The inhibitory effect of NHE inhibition on IL-8 was associated with a decrease in IL-8 mRNA accumulation. NHE inhibition suppressed both activation of the p42/p44 mitogen-activated protein kinase and nuclear factor-kappa B. Finally, NHE inhibition ameliorated the course of IBD in dextran sulfate-treated mice. Our data demonstrate that inhibition of NHEs may be an approach worthy of pursuing for the treatment of IBD.

cytokines; lipopolysaccharide; mitogen-activated protein kinase; Crohn's disease; ulcerative colitis


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