An investigation into the effect and mechanisms of action of nicotine in inflammatory bowel disease

Objective and Design: To determine the effect of nicotine on colonic inflam mation in the trinitrobenzenesulphonic acid (TNBS) model of inflammatory bo wel disease in comparison with sulphasalazine. Materials: Male Wistar rats were used for the in-vivo and exvivo studies. I n-vitro studies were performed using human leukemia peripheral blood monocy te cells (THP-1 cells) grown in continuous culture. Treatment: Rats were given access to either nicotine (5 or 100 mu g/mL) or sulphasalazine (375 mu g/mL) in their drinking water for 10 or 2 days respe ctively before and 3 days after TNBS administration. THP-1 cells were treat ed with nicotine (10(-14) to 10(-11) M) for 2h before and after stimulation with 3 mu g/mL lipopolysaccharide (LPS). Methods: Inflammation in the TNBS model was assessed by measuring the tissu e myeloperoxidase activity, leukotriene B-4 concentration, inducible nitric oxide protein expression, the ex-vivo production of tumour necrosis factor alpha (TNF alpha), macroscopic damage score, plasma corticosterone levels and by a qualitative histological evolution. The effect of nicotine on TNF alpha production in LPS stimulated THP-1 monocyte cells in-vitro was also d etermined. Statistical comparisons were made using the Mann-Whitney U-test for the macroscopic damage score and an ANOVA for all other parameters. Results. TNBS treated rats given access to 100 mu g/mL nicotine in their dr inking water had a marked reduction in several of the markers of inflammati on compared to control TNBS treated rats, but a greater reduction was found at 5 pg/mL, nicotine or 375 mu g/mL sulphasalazine, the latter producing c omparable reductions in inflammation to the low dose nicotine. Nicotine als o caused a significant reduction in TNF alpha release from THP-1 cells. Conclusions: Nicotine reduced inflammation in the TNBS model of colonic dam age confinning the use of nicotine in IBD although the choice of dose requi res further investigation. The mechanism of action of nicotine does not inv olve increased corticosterone levels, but may be a consequence of a reducti on in TNF alpha or leukotriene B-4 production.