Carbon monoxide produced by HO-1 upregulation is the main factor behind the abnormal motility seen in experimental ulcerative colitis in mice

The colonic motility is altered in patients with ulcerative colitis (UC), but the mechanism is not clear. Carbon monoxide (CO) is the molecule regulating the resting membrane potential (RMP) gradient across colonic smooth muscle wall. Changes in RMP will affect the contractility of smooth muscle. In this study, we investigated the altered colonic motility in dextran sodium sulfate-induced UC mice and the role of CO. The results showed that in the UC group, the frequency of spontaneous colonic contractions was increased while the AUC was decreased compared to the control group. HO-1, but not HO-2, positive cells were increased in the colonic smooth muscle wall of UC group. These HO-1 positive cells were mainly in the myenteric plexus and PGP9.5 positive, suggesting neuronal overproduction of CO. The RMP of circular smooth muscle cells (SMC) in the colon of UC group was hyperpolarized compared to that of control group. In control group, application of CORM-3, a CO donor, altered colonic spontaneous contractions by increasing their frequency and decreasing amplitude. In UC group, ZnPPIX, a HO-1 inhibitor, reduced the frequency and increased the amplitude. CORM-3 hyperpolarized the RMP of colonic SMC and abolished its gradient in control group, while ZnPPIX depolarized the RMP of colonic SMC and restored its gradient in UC group.

Conclusions: CO produced by HO-1 upregulation is the main factor behind the altered colinic motility seen in UC mice. CO is a potential candidate as a therapeutic target for patients with UC who suffer abnormal colonic motility.