Hydrogen peroxide inhibits Ca2+-dependent chloride secretion across colonic epithelial cells via distinct kinase signaling pathways and ion transport proteins.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Alfred E ChappellDeclan F McCole

Abstract

Reactive oxygen species (ROS) are key mediators in a number of inflammatory conditions, including inflammatory bowel disease (IBD). ROS, including hydrogen peroxide (H(2)O(2)), modulate intestinal epithelial ion transport and are believed to contribute to IBD-associated diarrhea. Intestinal crypt fluid secretion, driven by electrogenic Cl(-) secretion, hydrates and sterilizes the crypt, thus reducing bacterial adherence. Here, we show that pathophysiological concentrations of H(2)O(2) inhibit Ca(2+)-dependent Cl(-) secretion across T(84) colonic epithelial cells by elevating cytosolic Ca(2+), which contributes to activation of two distinct signaling pathways. One involves recruitment of the Ca(2+)-responsive kinases, Src and Pyk-2, as well as extracellular signal-regulated kinase (ERK). A separate pathway recruits p38 MAP kinase and phosphoinositide 3-kinase (PI3-K) signaling. The ion transport response to Ca(2+)-dependent stimuli is mediated in part by K(+) efflux through basolateral K(+) channels and Cl(-) uptake by the Na(+)-K(+)-2Cl(-) cotransporter, NKCC1. We demonstrate that H(2)O(2) inhibits Ca(2+)-dependent basolateral K(+) efflux and also inhibits NKCC1 activity independently of inhibitory effects on apical Cl(-) condu...Continue Reading

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Citations

Apr 9, 2014·The Journal of Physiology·Joseph B J WardStephen J Keely
Oct 27, 2015·Journal of Molecular Biology·Fernanda SchreiberTrevor D Lawley
Dec 19, 2014·Journal of Gastroenterology and Hepatology·Yasutada Akiba, Jonathan D Kaunitz
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Apr 27, 2017·Cardiovascular Research·Sofia-Iris BibliAndreas Papapetropoulos
Jan 13, 2021·Pharmaceutics·Mirna AlothmanMircea Alexandru Mateescu

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