Cholinergic pathways modulate experimental dinitrobenzene sulfonic acid colitis in rats.
Recent studies have suggested that neuroimmune interactions modulate intestinal mucosal immune responses. In the current study, we examined the role of cholinergic pathways in modulating the severity of acute dinitrobenzene sulfonic acid colitis, using pharmacological agents to suppress acetylcholinesterase in Sprague-Dawley rats, and evaluating the colitis in the cholinergic hyperresponsive Flinder's sensitive line rats and their control counterparts, the Flinder's resistant line. Colitis was induced by intrarectal dinitrobenzene sulfonic acid (80 mg x ml(-1) in 50% ethanol); controls received intrarectal saline. Sprague-Dawley rats received an acetylcholinesterase inhibitor, physostigmine (50 microg x kg(-1) s.c.) or neostigmine (50 microg x kg(-1) s.c.), 30 min prior to intrarectal dinitrobenzene sulfonic acid; controls received saline vehicle. On day 5, the macroscopic damage score, myeloperoxidase activity (an estimate of granulocyte infiltration) and smooth muscle thickness were evaluated in the inflamed colonic segment. Significant increases in macroscopic damage score and colonic smooth muscle thickness were observed in Sprague-Dawley and Flinder's Resistant Line rats on day 5 following intrarectal dinitrobenzene sulfonic acid compared to saline controls. Increased myeloperoxidase activity was also observed in dinitrobenzene sulfonic acid-treated Sprague-Dawley rats and Flinder's Resistant Line rats. In contrast, Flinder's Sensitive Line rats failed to demonstrate a significant rise in macroscopic damage, smooth muscle layer thickness, or myeloperoxidase activity on day 5 following intrarectal dinitrobenzene sulfonic acid when compared to saline-treated Flinder's Sensitive Line controls. Neostigmine and physostigmine treatment prior to intrarectal dinitrobenzene sulfonic acid significantly attenuated macroscopic damage score, myeloperoxidase activity and smooth muscle thickness on day 5 compared to colitic Sprague-Dawley controls. Significantly greater reductions in myeloperoxidase activity were observed with physostigmine vs. neostigmine pretreatment. These data suggest that cholinergic pathways modulate the acute colonic inflammatory response associated with the dinitrobenzene sulfonic acid model, with central pathways exerting a greater protective effect relative to peripheral pathways. Further studies are required to determine the contributions of sites in the nervous system and neuro-effector junctions.
Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada.
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Miceli
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Jacobson
D000818:Animals; D001557:Benzenesulfonates / Q000633:toxicity*; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001557:Benzenesulfonates; D018721:Muscarinic Agonists; C007488:dinitrobenzenesulfonic acid; D009195:Peroxidase