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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

NAD⁺ Ameliorates Inflammation-Induced Epithelial Barrier Dysfunction in Cultured Enterocytes and Mouse Ileal Mucosa

Departments of Critical Care Medicine (X.H., T.U., P.L.S., A.Y., M.P.F., R.L.D.), Pathology (R.L.D.), and Surgery (M.P.F.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

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-, interleukin-1, and tumor necrosis factor-. 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-B (NF-B) 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-B activation and increased NO· production.

Address correspondence to: Dr. Russell L. Delude, 615 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. E-mail: deluder{at}ccm.upmc.edu

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