Suppression of pro-inflammatory cytokine release by selective inhibition of inducible nitric oxide synthase in mucosal explants from patients with ulcerative colitis

Background: In ulcerative colitis (UC), inflammatory damage is associated with increased production of pro-inflammatory cytokines and nitric oxide through the inducible nitric oxide synthase (iNOS) pathway. In an animal model of acute experimental colitis we have previously shown amelioration of inflammation with the highly selective iNOS inhibitor 1400 W. The aim of the present study was to investigate the effects of selective iNOS inhibition on the production of pro-inflammatory cytokines by the colon mucosa in UC. Methods: Inflamed and uninflamed mucosa from patients with severe UC were incubated with a highly selective iNOS inhibitor N-[3-(aminomethyl)benzyl]acetamidine (1400 W), with a relatively selective cNOS inhibitor N(G)-nitro-L-arginine-methyl-esther (L-NAME), or with an NO-donor, S-nitroso-acetylpenicillamine (SNAP). Cytokine concentrations in the incubation medium were quantitated with ELISA. Results: Compared to uninflamed mucosa there was an increase in iNOS protein and nitrotyrosine levels...