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Hemin reduces postoperative ileus in a heme oxygenase 1-dependent manner while dimethyl fumarate does without heme oxygenase 1-induction.

Abstract

BACKGROUND

Postoperative ileus (POI), the impairment of gastrointestinal motility after abdominal surgery, is mainly due to intestinal muscular inflammation. Carbon monoxide (CO)-releasing compounds were shown to exert an anti-inflammatory effect in murine POI partially through induction of heme oxygenase-1 (HO-1). The influence of hemin and dimethyl fumarate (DMF), currently used for multiple sclerosis (MS), was therefore tested in murine POI.

METHODS

C57BL/6J mice were anesthetized and after laparotomy, POI was induced via intestinal manipulation (IM). Animals were treated with either 30 mg kg-1 hemin intraperitoneally (ip), 30 mg kg-1 DMF ip, or 100 mg kg-1 intragastrically (ig) 24 hours before IM. Intestinal transit was assessed 24 hours postoperatively and mucosa-free muscularis or whole segments of the small intestine were stored for later analysis. Intestinal HO-1 protein expression was studied at 6, 12, and 24 hours after administration of hemin or DMF in non-manipulated mice.

KEY RESULTS

Pretreatment with hemin and DMF, both ig and ip, prevented the delayed transit seen after IM. Concomitantly, both hemin and DMF significantly reduced the increased interleukin-6 levels and the elevated leukocyte infiltration in the muscularis. Hemin but not DMF caused a significant increase in intestinal HO-1 protein expression and co-administration of the HO-1 inhibitor chromium mesoporphyrin abolished the protective effects of hemin on POI; DMF reduced the IM-induced activation of NF-κB and ERK 1/2.

CONCLUSIONS AND INFERENCES

Both hemin and DMF improve the delayed transit and inflammation seen in murine POI, but only hemin does so in a HO-1-dependent manner.

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  • Authors+Show Affiliations

    ,

    Department of Basic and Applied Medical Sciences, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium.

    ,

    Department of Human Structure and Repair, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium.

    ,

    Unit of Molecular Signal Transduction in Inflammation, Center for Inflammation Research, VIB, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

    Department of Basic and Applied Medical Sciences, Faculty of Medicine & Health Sciences, Ghent University, Ghent, Belgium.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31121086

    Citation

    Van Dingenen, Jonas, et al. "Hemin Reduces Postoperative Ileus in a Heme Oxygenase 1-dependent Manner While Dimethyl Fumarate Does Without Heme Oxygenase 1-induction." Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, 2019, pp. e13624.
    Van Dingenen J, Pieters L, Van Nuffel E, et al. Hemin reduces postoperative ileus in a heme oxygenase 1-dependent manner while dimethyl fumarate does without heme oxygenase 1-induction. Neurogastroenterol Motil. 2019.
    Van Dingenen, J., Pieters, L., Van Nuffel, E., & Lefebvre, R. A. (2019). Hemin reduces postoperative ileus in a heme oxygenase 1-dependent manner while dimethyl fumarate does without heme oxygenase 1-induction. Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society, pp. e13624. doi:10.1111/nmo.13624.
    Van Dingenen J, et al. Hemin Reduces Postoperative Ileus in a Heme Oxygenase 1-dependent Manner While Dimethyl Fumarate Does Without Heme Oxygenase 1-induction. Neurogastroenterol Motil. 2019 May 23;e13624. PubMed PMID: 31121086.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Hemin reduces postoperative ileus in a heme oxygenase 1-dependent manner while dimethyl fumarate does without heme oxygenase 1-induction. AU - Van Dingenen,Jonas, AU - Pieters,Leen, AU - Van Nuffel,Elien, AU - Lefebvre,Romain A, Y1 - 2019/05/23/ PY - 2018/08/08/received PY - 2019/03/28/revised PY - 2019/04/26/accepted PY - 2019/5/24/entrez PY - 2019/5/24/pubmed PY - 2019/5/24/medline KW - dimethyl fumarate KW - heme oxygenase-1 KW - hemin KW - mouse KW - postoperative ileus SP - e13624 EP - e13624 JF - Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society JO - Neurogastroenterol. Motil. N2 - BACKGROUND: Postoperative ileus (POI), the impairment of gastrointestinal motility after abdominal surgery, is mainly due to intestinal muscular inflammation. Carbon monoxide (CO)-releasing compounds were shown to exert an anti-inflammatory effect in murine POI partially through induction of heme oxygenase-1 (HO-1). The influence of hemin and dimethyl fumarate (DMF), currently used for multiple sclerosis (MS), was therefore tested in murine POI. METHODS: C57BL/6J mice were anesthetized and after laparotomy, POI was induced via intestinal manipulation (IM). Animals were treated with either 30 mg kg-1 hemin intraperitoneally (ip), 30 mg kg-1 DMF ip, or 100 mg kg-1 intragastrically (ig) 24 hours before IM. Intestinal transit was assessed 24 hours postoperatively and mucosa-free muscularis or whole segments of the small intestine were stored for later analysis. Intestinal HO-1 protein expression was studied at 6, 12, and 24 hours after administration of hemin or DMF in non-manipulated mice. KEY RESULTS: Pretreatment with hemin and DMF, both ig and ip, prevented the delayed transit seen after IM. Concomitantly, both hemin and DMF significantly reduced the increased interleukin-6 levels and the elevated leukocyte infiltration in the muscularis. Hemin but not DMF caused a significant increase in intestinal HO-1 protein expression and co-administration of the HO-1 inhibitor chromium mesoporphyrin abolished the protective effects of hemin on POI; DMF reduced the IM-induced activation of NF-κB and ERK 1/2. CONCLUSIONS AND INFERENCES: Both hemin and DMF improve the delayed transit and inflammation seen in murine POI, but only hemin does so in a HO-1-dependent manner. SN - 1365-2982 UR - https://www.unboundmedicine.com/medline/citation/31121086/Hemin_reduces_postoperative_ileus_in_a_heme_oxygenase_1-dependent_manner_while_dimethyl_fumarate_does_without_heme_oxygenase_1-induction L2 - https://doi.org/10.1111/nmo.13624 DB - PRIME DP - Unbound Medicine ER -