6th Annual BMRP Investigator Meeting - Abstract

To Examine the Therapeutic Potential of a Novel Mucosal Barrier-Inducing Factor in the Treatment of Crohn’s Disease

Tor Savidge^1,a, Petri Urvil¹, Jonathan Meddings², Jonathan Stamler³, Joseph Sellin<sup>1

1</sup>Department of Gastroenterology and Hepatology, University of Texas Medical Branch (Galveston, Texas, U.S.A.); ²Department of Medicine, University of Alberta (Edmonton, Canada); ³Department of Medicine, Duke University (Durham, North Carolina, U.S.A.) 

Intestinal barrier dysfunction occurs in patients with inflammatory bowel disease and may contribute towards disease-activity. We have recently identified S-nitrosoglutathione (GSNO) as a novel glial-derived regulator of intestinal barrier functionandinflammation. Small S-nitrosothiols, principally GSNO, mediate many complex biological responses of nitric oxide (NO) by transferring an NO⁺ group to functionally important cysteine residues forming an S-nitrosothiol (SNO). Thus, S-nitrosylation functions in a manner analogous to post-translational phosphorylation and can drastically alter protein function. Deficiencies in SNO production have recently been shown to contribute to inflammatory pathogenesis in CNS, respiratory and cardiovascular disease. We have therefore tested a new related hypothesis that a deficiency in the SNO-effector system also contributes to the primary intestinal barrier dysfunction in Crohn’s disease. Our preliminary data demonstrates that the colonic GSNO-effector system is significantly disrupted in Crohn’s disease patients with tissue GSNO levels, and g-glutamyl transpeptidase and GSNO-reductase enzyme expression showing disease-specific expression.  Furthermore, we have demonstrated that the colitis-induced pore-forming tight junction protein claudin-2 is dramatically up regulated in Crohn’s disease patients, and is a potential therapeutic target for S-nitrosylation as GSNO inhibits the disease-associated activity of this protein.

^aPrincipal Investigator