Mechanisms of the gastrointestinal motility dysfunction under septic conditions - a role of Interstitial Cells of Cajal -

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Patients with severe sepsis frequently accompany gastrointestinal dysfunction such as paralytic ileus. The latter is thought to induce bacterial translocation, which may aggravate septic states of the patients. The mechanism of gastrointestinal motor dysfunction, however, is still unknown. Interstitial cells of Cajal (ICC) generate electric slow wave and thus are considered gastrointestinal pacemaker cells. We have investigated the mechanism of ICC injury under septic conditions using lipopolysaccharide (LPS)-injection model of mouse. Intraperitoneal injection of LPS decreased spontaneous intestinal movement, dose- and time- dependently. Similar results were obtained by measuring electric activity of electric slow wave. LPS also induced activation of macrophages and induction of iNOS in them. i.p. injection of LPS also caused decrease in KIT-positive cells in and around the myenteric plexus, LPS-induced decrease in both spontaneous intestinal movement and the KIT-positive cell number was restored by pretreatment of Gadlinium and addition of iNOS inhibitors. The additions of NO releaser, FK409, caused abrupt decrease in spontaneous intestinal movement in vitro. In vivo addition of FK409 caused decrease in both spontaneous intestinal movement and the KIT-positive cell number. The present results indicate that NO produced by iNOS, which is induced in activated macrophages by LPS, caused ICC injury, resulting in decrease in spontaneous intestinal movement and thus LPS-induced intestinal dysfunction.