PT - JOURNAL ARTICLE AU - Xiaonan Han AU - Takashi Uchiyama AU - Penny L. Sappington AU - Arino Yaguchi AU - Runkuan Yang AU - Mitchell P. Fink AU - Russell L. Delude TI - NAD<sup>+</sup> Ameliorates Inflammation-Induced Epithelial Barrier Dysfunction in Cultured Enterocytes and Mouse Ileal Mucosa AID - 10.1124/jpet.103.056556 DP - 2003 Nov 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 443--449 VI - 307 IP - 2 4099 - http://jpet.aspetjournals.org/content/307/2/443.short 4100 - http://jpet.aspetjournals.org/content/307/2/443.full SO - J Pharmacol Exp Ther2003 Nov 01; 307 AB - In the course of other experiments, we serendipitously observed that extracellular nicotinamide adenine dinucleotide (NAD+) ameliorated the development of epithelial hyperpermeability when monolayers of Caco-2 enterocyte-like cells were incubated with cytomix, a mixture containing interferon-γ, interleukin-1β, and tumor necrosis factor-α. We sought to characterize the effects of NAD+ on inflammation-induced epithelial barrier dysfunction using Caco-2 monolayers that were exposed to cytomix in the absence or presence of NAD+ or other purine-containing molecules. Paracellular barrier function measured as the apical-to-basolateral passage of fluorescein isothiocyanate-conjugated dextran (mol. wt. ∼4000) was preserved in a concentration-dependent manner when immunostimulated Caco-2 cells were exposed to extracellular NAD+. Incubation with NAD+ prevented cytomix-induced derangements in the expression and localization of the tight junction proteins occludin and zonula occludens-1 in Caco-2 cells. Treatment of cytomix-stimulated cells with NAD+ also blocked nuclear factor-κB (NF-κB) activation, inducible nitric-oxide synthase induction, and increased production of nitric oxide (NO·). Ileal mucosal permeability to fluorescein isothiocyanate-dextran mol. wt. ∼4000 was increased in mice 18 h after lipopolysaccharide (endotoxin) injection, but treatment of endotoxemic mice with NAD+ ameliorated the development of gut mucosal hyperpermeability. Thus, extracellular NAD+ seems to ameliorate inflammation-induced intestinal epithelial barrier dysfunction by inhibiting NF-κB activation and increased NO· production. The American Society for Pharmacology and Experimental Therapeutics