Animal in Vivo and in Vitro Studies

As already described, the mechanisms of altered motility in IBD are unclear but may reflect changes in the axon/smooth muscle cell relationship and data suggest that the enteric nervous system (ENS) has an important role in the motility defects [68]. A limitation in understanding the etiology of IBD is that few animals spontaneously develop colitis and several animal models, particularly the hapten 2,4,6-trini-trobenzenesulfonic acid (TNBS) in ethanol have been used to produce an acute inflammation that progresses over several weeks to a chronic stage that is morphologically similar to Crohn's disease. Data in animal models are controversial. Measurements of In Vivo motility patterns in dogs during acetic acid-induced ileitis showed that inflammation increased the frequency of giant migrating contractions and decreased the frequency of migrating motor complexes and tone [69, 70]. A study evaluating colonic motor response to a meal in acute colitis dogs showed an absence of motor response of the colon to a meal and increase in the postprandial frequency of giant migrating contractions associated with an increase in defecation frequency [71]. Data suggest that both the initial inflammation and recurrence of active disease induce a transient increase in contractile amplitude and duration and the effects of repeated episodes of acute inflammation (i.e., successive applications of TNBS in rats) have a different impact on spontaneous contractions of colonic circular muscle compared with a single TNBS application [72]. Acute inflammation of the colon significantly promotes the amplitude and duration of spontaneous contractions likely due to loss of NO control or to changes in excitatory neurotransmitters such as acetylcholine (Ach) [72]. Whereas, other data suggest that propulsive motility is reduced, since in rats with acute dextran sulfate sodium (DDS)-induced colitis, there was a reduced frequency of colonic giant migrating contractions in the proximal and middle colon [73] and reduced pellet propulsion In Vitro in isolated distal colon from TNBS-treated guinea pigs [74].

Many of the contractile abnormalities of muscle from animal models of colitis appear to be due to muscle specific defects, or alterations in signal trans-duction mechanisms rather than plasticity of the innervation of the muscle [75-77]. Indeed, morphological studies of canine colon suggest that NO is a crucial mediator in the communication between interstitial cells of Cajal, enteric inhibitory nerves, and smooth muscle in the generation of spontaneous contractions [78]. Impaired nitric oxide synthase (NOS) activity in nerves seems to be implicated in the reduced ability of smooth muscle to relax in colitis induced by dextran sulfate sodium in rats [79]. Modifications in excitatory reactions are illustrated by data showing an increased response to ACh and substance P during acute inflammation, an effect attributed to a loss of neural inhibition (i.e., NOS activity), rather than an increase in excitation, resulting in enhanced contractile amplitude [80].

The initial inflammation induces a long-lasting alteration in the frequency of spontaneous contractions, which suggests a remodeling of the interactions between smooth muscle and nerves. In TNBS colitis in the rat, it has been recently demonstrated that a loss of intrinsic axons is an early event in colitis and, although reversed by axonal proliferation, transient denervation may promote circular smooth muscle cell hyperplasia [81].

Specifically, chronic inflammation reduces smooth muscle contractility [80], and the thickening of the smooth muscle evident at 7 days post TNBS is consistent with reports of smooth muscle hyperpla-sia and hypertrophy in animal models [82] and in IBD patients [83].

In experiments with injections of indomethacin in rats, which induces inflammation, during the active phase there is a decrease of motor activity related to bacterial translocation [84]. The initial intestinal hypomotility seems associated to inhibitory effects of nitric oxide due to the increased levels of inducible NOS isoform, since after the administration of selective iNOS inhibitors, a reaction of hypermotility occurs. Nematode infection leads to direct effects of Th2 cytokines such as myocyte hypertrophy and hypercontractility similar to that seen because of exposure to IL-4 and IL-13 and is thought to be partly due to the signal transducer and activator of transcription factor STAT-6 in the affected myocytes, which is necessary for the effect of Th2 cytokines [85]. The impact of chronic inflammation on muscle contractility has been examined after 12 weeks of infection with Schistosoma mansoni in mice [86] and pigs [87]. The infection in the mice caused small intestinal hypercontractility on one side, that seemed to be due to increased postjunctional myocyte responsiveness to a released transmitter and a slow transit on the other side [86]. In the pigs, the severity of infection was inversely correlated with VIP immunoreactivity and directly correlated with SP and neuronal nitric oxide synthase (nNOS) levels [88].

In summary, as already stated, several factors contribute to alteration of muscle contractility. Some changes are due to prereceptor mechanisms, causing a reduced release of non-adrenergic, non-cholinergic inhibitory transmitters that diminish contractility and relaxation of the non-inflamed fundus in TNBS ileitis in rats. In fact, changes in muscle function are not limited to the region of the inflamed gut [89, 90]: noradrenaline and acetylcholine are reduced not only in the inflamed, but also in the unaffected segment in TNBS colitic rats. The reduced release of neurotransmitters during colitis can be explained by increased presynaptic inhibition of neurotransmitter release, either by augmented a2-adrenoceptor expression or by enhanced release of histamines from mast cells and elevated levels of cytokines such as IL-6 [91]. As well as in humans, stress has effects on the GI tract in animals. Gastrointestinal transit is differently affected by stress, varying from region to region: specifically the orocecal and colonic transit was accelerated, while gastric emptying was delayed [92].

Acute tissue irritation with chemical irritants such as turpentine, acetic acid, formalin, or zymosan induces visceral hyperalgesia in animal models of acute colitis, mediated by the activity of spinal N-methyl d-aspartate (NMDA) and non-NMDA receptors, as well as in rats treated with TNBS there is an enhanced visceromotor response to colorectal distension [93].

The reduced contractile activity in IBD [94] may be the result of altered serotonin (5-HT) availability (increase 5-HT availability and decrease 5-HT reuptake), likely due to desensitization of 5-HT receptors. These data suggest that abnormal 5-HT signaling at the afferent limb of intrinsic and extrinsic reflex pathways, due to increased 5-HT availability, could contribute to changes in gut function and sensitivity in the inflamed bowel [95].

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