Human In Vitro Studies

The mechanisms underlying this colonic dysfunction are poorly understood, but may involve changes in smooth muscle contractility, enteric neurotransmission or afferent sensory input from the bowel wall. It is well recognized that inflammation is associated with alterations in mucosal and motor function in both the small intestine and the colon and that colonic motility varies with disease activity. As inflammation progresses, there are changes in the profile of the inflammatory/immune cells and associated mediators that may directly or indirectly affect smooth muscle contractility. Early clinical studies report both hypermotility and hypomotility in ulcer-ative colitis patients. Moreover, UC patients exhibit changes in the frequency of spontaneous contractions that vary with the duration of their disease. A number of studies have attempted to determine whether neurotransmission and neuromuscular function is altered in the colonic tissue of IBD-affect-ed patients. The intrinsic properties of the circular muscle from patients with UC show few differences from those of healthy control subjects, but electrically or agonist-stimulated contraction are reduced [36, 37]. Altered motor function measured In Vitro may be evident through alterations in the cholinergic function or neurokinin (NK) receptor-mediated contraction in the smooth muscles in UC [38]. Extrinsic sensory neurons in the gut contain neurotransmit-ters such as calcitonin gene-related peptide (CGRP) and substance P (SP). Both have been implicated in the effects of colonic distension and capsaicin application to the colon and are considered to have an important role in normal digestive, secretory and motor functions in the gut [39, 40]. There is also strong evidence implicating sensory neuropeptides in the functional development of gastrointestinal inflammation, particularly in IBD [41]. Elevations of substance P (SP) peptide levels and immunoreactivi-ty [42-43], and upregulation of receptors for SP and its mRNA [44, 45], influence inhibitory nerves including nerves containing vasoactive intestinal peptide (VIP). Reduction in excitatory transmit including SP [46] and altered NK-2 receptor-mediated contraction occur in IBD-affected colon [47].

Selective impairments in tachykinin and CGRP-mediated colonic motility are manifest in inflammatory bowel disease In Vitro [48]. Data show a reduction in motility in patients with active disease. In Vitro, there is evidence of impaired contractility of smooth muscle from UC patients, suggesting the physiological release of an inhibitory neurotransmitter [36]. There is a large neural inhibitory component to responses from inflamed tissue and these responses could be blocked through the inhibition of nitric oxide synthase (NOS), implicating nitric oxide (NO) as the mediator [49]. The role of NO in the patho-physiology of IBD is controversial. An immunoblot of biopsies revealed significant elevation of nitric oxide synthase isoform (iNOS) in active UC compared to uninflamed sites [50, 51], whereas in patients with CD, no significant changes were detected [52].

Recently, using a new investigative tool (chemilu-minescence technique by means of a tonometric balloon), some authors detected higher rectal luminal levels of NO in IBD patients compared to IBS and healthy controls [53]. Nicotine appears to reduce circular muscle activity, predominantly through the release of NO that appears to be upregulated in active ulcerative colitis [54].

There is an increase in NO synthase activities in the nerve of the myenteric plexus as well as in smooth muscle cells in the colon in UC [55]. A report evaluating expression of the inducible isoform of nitric oxide synthase (iNOS) in UC suggested increased production of this inflammatory enzyme in the muscle layers of the colon and implicated the resultant nitric oxide as the mediator of the reduced contractility and consequent toxic megacolon [56].

One of the mechanisms responsible for the motil-ity dysfunction observed in patients with UC could be due to increase level of cytokines (i.e., IL-1 beta) through production of hydrogen peroxide (H2O2) [57]. In UC, the mucosa releases IL-lbeta, H2O2, and NO [58], and H2O2 is also produced in the muscle layer of UC [59], which may contribute to the impaired Ca2+ release and altered sigmoid muscle contractility. In both human and animal models of colitis there appears to be a relationship between altered colonic motility and abnormal local release of various inflammatory mediators of which prostaglandins such as PGE2 are of considerable importance [60, 61]. There is evidence of increased synthesis of prostaglandin (PGE2) in the rat myen-teric plexus after appropriate cytokine stimulation [62] and also in the rectal mucosa of patients with active IBD [63].

Gastrin releasing peptide (GRP) receptor expres sion is decreased in the inflamed and non-inflamed colon of CD, while that is not the case in UC [64]. The cell types involved in the altered motor pattern include interstitial cells of Cajal [65], which are damaged and presumably contribute to altered motility. In tissues from Crohn's disease patients, the density of interstitial cells of Cajal is reduced throughout the tunica muscularis, suggesting that the disturbance of intestinal motility that occurs in patients with CD may be a consequence of the loss of or defects in specific populations of interstitial cells of Cajal within the tunica muscularis [66]. Hypersensitivity to cholinergic stimulation has been demonstrated in the colonic smooth muscle from patients with UC and it may result from increased calcium release from intracellular stores [67].

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