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Water-soluble CO-releasing molecules (CO-RMs) reduce the development of postoperative ileus via modulation of MAPK/HO-1 signaling and reduction of oxidative stress
  1. Ole De Backer (ole.debacker{at}
  1. Ghent University, Belgium
    1. Ellen Elinck
    1. Ghent University, Belgium
      1. Bart Blanckaert
      1. Ghent University, Belgium
        1. Luc Leybaert
        1. Ghent University, Belgium
          1. Roberto Motterlini
          1. Northwick Park Institute for Medical Research, United Kingdom
            1. Romain A Lefebvre
            1. Ghent University, Belgium


              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.

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