Exogenous Vasoactive Intestinal Peptide Maintains Colon Mucosal Lining in Experimental Colitis Models by Attenuating Colonic Mitochondrial Dysfunction through Scavenging of Superoxide and Hydroxyl Radicals: Implications in Ulcerative Colitis.

Background/Aims Vasoactive intestinal peptide (VIP) has emerged as a promising agent for treatment of inflammatory bowel disease; however, its impact in ulcerative colitis (UC) targeting colonic mitochondrial dysfunction for maintenance of colon epithelial tract remains uninvestigated. Methods Two working models are as follows. In vivo model: DSS was administered in C57BL/6J mice @ 3.5%/gm body weight for three cycles of 5 days each (5 days gap in between each cycle); i.p. dose of VIP @ 0.5 nmol/mouse/day was administered for next 10 days. Posttreatment mice were sacrificed and isolated mitochondria were utilized for experimentation. In vitro model: to substantiate in vivo findings and accurately identify the reactive species involved in progression of UC, HT29 MTX-E12 mucosal model depicting semi-wet interface as in colon, was subjected to DSS (5%) treatment for 6 days followed by VIP (10 nM) treatment for 4 days in presence and absence of O2 •- scavenger superoxide dismutase (SOD; 20 mM) or •OH scavenger dimethyl sulfoxide (DMSO; 20 mM) or H2O2 scavenger catalase (CAT; 50 μg/mL) or nitric oxide (NO) scavenger L-NAME (100 μM) or ONOO- scavenger cum nitric oxide synthase inhibitor MEG (0.5 mM). Results In vivo: treatment with VIP reduced clinical and histopathological severity of DSS-induced colitis with partial recovery of inhibited mitochondrial respiratory complexes, altered mitochondrial membrane potential and lowered ATP generation. Amelioration of mitochondrial oxidative stress variables were also observed following VIP treatment. In vitro: treatment with VIP restored mitochondrial dysfunction and its efficacy proved at par with SOD and DMSO indicating involvement of O2 •- and •OH in the process. However, other free radical scavengers/inhibitors like CAT, L-NAME and MEG proved ineffective indicating non-involvement of H2O2, NO and ONOO- in the process. Conclusions VIP can act as potent anticolitogenic agent by virtue of its free radical scavenging property as it restored colonic mitochondrial function that contributed in maintenance of colon epithelial lining following exogenous VIP treatment. [ABSTRACT FROM AUTHOR]