Mechanism of abnormal intestinal motility in inflammatory bowel disease: how smooth muscle contraction is reduced?

Abstract

Intestinal inflammation alters the contractile activity of intestinal smooth muscle. Motility disorders of the gastrointestinal tract are clinically important symptoms, because they are often associated with severe interstitial inflammation. In addition, the motility disorders secondarily induce abnormal growth of the intestinal flora, and the resulting disturbance of this flora aggravates the pathogenesis of mucosal inflammation. This in turn aggravates the intestinal dysmotility; i.e., it is an inflammatory spiral. Therefore, it is important to elucidate the mechanisms involved in the changes in motor function which occur in intestinal inflammation. Recent studies have revealed several molecular mechanisms responsible for the decreased motility which occurs in an inflamed gastrointestinal tract. In the present review, we discuss the functional failure of smooth muscle cells, including changes in the activity of muscarinic receptors, ion channels and the endogenous myosin phosphatase inhibitor CPI-17.Key words: intestinal inflammation, smooth muscle, contraction, CPI-17 Motility disorders in intestinal inflammationMotility disorders of the gastrointestinal tract are extremely important clinically because they can lead to systemic disease. In humans and in animal models, intestinal inflammation results in the disturbance of motility, which may reflect changes in smooth muscle function and/or the enteric nervous system (Vermillion et al., 1993;Vrees et al., 2002). Both increased and decreased smooth muscle contractility has been observed in intestinal inflammation. In a model of nematode infection-induced gut inflammation, such as Trichinella spiralis infectioninduced gut inflammation, smooth muscle contractility is increased (Vermillion and Collins, 1988;Blennerhassett et al., 1992). On the other hand, smooth muscle contractility is decreased T. OHAMA et al. 44 in the intestinal inflammation induced by trinitrobenzene sulphonic acid (TNBS), surgical manipulation, experimental obstruction, hemorrhagic shock, or peritonitis (Kalff et al., 1998;Moreels et al., 2001; Koyluoglu et al., 2002;Hierholzer et al., 2004; Kinoshita et al., 2006; Kiyosue et al., 2006;Won et al., 2006; Kinoshita et al., 2007;Ohama et al., 2007b). These differences in contractile responses may be due to differences in cytokine profiles. Reports from the Collins group (Akiho et al., 2002;Akiho et al., 2005a;Akiho et al., 2005b) have suggested that nematode-induced hypercontractility is mediated by an increase in prostaglandin E2 (PGE2) levels after induction of the expression of Th2 cytokines such as interleukin (IL)-4 and IL-13.On the other hand, reports suggest that TNBS-induced gut inflammation is mediated mainly by Th1 cytokines such as IL-1β, tumor necrosis factor-α (TNF-α) and IL-12 (Neurath et al., 1995; Kinoshita et al., 2006; Kiyosue et al., 2006;Ohama et al., 2007b). In this review, we focused on the molecular mechanisms that are responsible for the decreased motility of the inflamed intestine. Nematode-induced hyper-co...

Mechanisms of gastric emptying disturbances in chronic and acute inflammation of the distal gastrointestinal tract

“…Although there is ample evidence from animal experiments that gastrointestinal motility including gastric emptying is altered by intestinal inflammation (43), pathomechanisms causing delayed gastric emptying in inflammatory diseases of the human distal gastrointestinal tract have not been investigated, so far. Specifically in CD, duodenal obstruction might impede gastric emptying; however, duodenal obstruction is a rare condition, none of our patients had evidence of upper gastrointestinal obstruction, and delayed gastric emptying has been demonstrated in patients with nonobstructive CD before (2).…”

Cytokine-Induced S-Nitrosylation of Soluble Guanylyl Cyclase and Expression of Phosphodiesterase 1A Contribute to Dysfunction of Longitudinal Smooth Muscle Relaxation

“…activity of various signaling molecules that regulate smooth muscle contraction and relaxation (Akiho et al, 2002;Shi et al, 2003;Cao et al, 2004;Jin et al, 2004;Salinthone et al, 2004;Singer et al, 2004;Shi and Sarna, 2005;Zhao et al, 2005Zhao et al, , 2006Khan and Collins, 2006;Ohama et al, 2007;Ihara et al, 2012;Shea-Donohue et al, 2012;Yang et al, 2013). Previous studies have identified that signaling pathways that mediate initial and sustained contraction in intestinal longitudinal muscle are distinct from those in circular muscle (Grider and Makhlouf, 1988;Murthy, 2006).…”

Alterations of Colonic Contractility in an Interleukin-10 Knockout Mouse Model of Inflammatory Bowel Disease

“…14 Although many studies have been conducted to investigate digestive tract motility using various animal models, [15][16][17][18][19][20][21][22][23][24] few studies have been conducted using IL-10 −/− mice. Accordingly, this study was conducted to investigate changes in colonic contractility in IL-10 −/− mice and the possible mechanisms of these changes.…”