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.

Postoperative ileus: A pharmacological perspective

“…The mechanisms of CO action have been described and reviewed in depth by Babu et al The mechanisms of action of CO on postoperative ileus at MAPK level include suppression of ERK MAPK phosphorylation via a soluble guanine cyclase (sGC)‐dependent pathway and induction of haem oxygenase 1 (HO1) via phosphorylation of p38 MAPK (Babu et al, 2015). More recently, the direct induction of HO1 and its anti‐inflammatory and postoperative ileus‐preventing action have been reported in mice following the intraperitoneal administration of Hemin (Van Dingenen et al, 2020).…”

“…The mechanisms of CO action have been described and reviewed in depth by Babu et al, 2015). More recently, the direct induction of HO1 and its antiinflammatory and postoperative ileus-preventing action have been reported in mice following the intraperitoneal administration of Hemin (Van Dingenen et al, 2020).…”

Heme Oxygenase-1 in Gastrointestinal Tract Health and Disease

“…Another study carried out by De backer and colleagues showed similar effects using water-soluble-CO releasing molecules, but in this case the protective effects described are mediated in part by a p38-dependent induction of HO-1 and a decrease of ERK1/2 activation [161]. A more recent study used hemin pre-treatment as POI therapy, improving digestive motility through an increase of HO-1, and a reduction of leukocyte infiltration and IL-6 [162].…”

Postoperative ileus—An ongoing conundrum

“…In one study, pretreatment of mice with hemin prevented post-surgery induced delayed intestinal transit. 114 As yet this has not been tested in humans.…”