Background and aims: Treatment with CO-inhalation has been shown to ameliorate postoperative ileus (POI) in rodents and swine. The aim of this study was to investigate whether CO liberated from water-soluble CO-releasing molecules (CO-RMs) can protect against POI in mice and to elucidate the mechanisms involved.
Methods: Ileus was induced by surgical manipulation of the small intestine (IM). Intestinal contractility-transit was evaluated by video-fluorescence imaging. Leukocyte infiltration (myeloperoxidase), inflammatory parameters (ELISA), oxidative stress (lipid peroxidation), and heme oxygenase (HO)/inducible NO synthase (iNOS) enzyme activity were measured in the intestinal mucosa and muscularis propria.
Results: Intestinal contractility and transit were markedly restored when manipulated mice were pre-treated with CO-RMs. Intestinal leukocyte infiltration, expression levels of IL-6, MCP-1 and ICAM-1, as well as iNOS activity were reduced by CORM-3-treatment; whereas expression of IL-10/HO-1 was further increased when compared to non-treated manipulated mice. Moreover, CORM-3-treatment markedly reduced oxidative stress and ERK1/2 activation in both mucosa (early response) and muscularis (biphasic response). The p38 MAPK-inhibitor SB203580 abolished CORM-3-mediated HO-1-induction. The HO-inhibitor CrMP only partially reversed the protective effects of CORM-3 on inflammation/oxidative stress in the muscularis, but completely abrogated CORM-3-mediated inhibition of the early 'oxidative burst' in the mucosa.
Conclusions: Pre-treatment with CO-RMs markedly reduced IM-induced intestinal muscularis inflammation. These protective effects are, at least in part, mediated through induction of HO-1 - in a p38-dependent manner - as well as reduction of ERK1/2 activation. In addition, CORM-induced HO-1 induction reduces the early 'oxidative burst' in the mucosa following IM.