J. VAN DINGENEN (1), R. LEFEBVRE (1) / [1] Ghent University, Ghent, Belgium, Department of Pharmacology - Heymans Institute
Introduction Heme oxygenase (HO) catalyzes the degradation of heme into ferrous iron, carbon monoxide (CO) and biliverdin, which is subsequently reduced to bilirubin; bilirubin and CO have anti-oxidative and anti-inflammatory properties. The inducible isoform HO-1 is expressed in reaction to oxidative stress and inflammation, contributing to tissue protection in these conditions. Postoperative ileus (POI), the impairment of gastrointestinal motility after abdominal surgery, is mainly due to intestinal muscular inflammation triggered by surgical handling. It was already shown that CO-releasing compounds exert an anti-inflammatory effect in murine POI partially through induction of HO-1. Dimethyl fumarate (DMF) is currently used to treat patients with multiple sclerosis or psoriasis. In vitro it is a very effective inducer of HO-1 and preclinical studies suggest that its immunosuppressive and neuroprotective effects are related to induction of HO-1.
Aim
The aim of this study was therefore to investigate the effect of DMF on the intestinal inflammation and on the delay in gastrointestinal transit caused by POI.
Methods C57Bl6J mice were anesthetized (isoflurane) and after laparotomy, POI was induced by compressing the small intestine with cotton applicators (intestinal manipulation; IM) for 5 min. DMF was administered intragastrically (100 mg/kg) via gavage or intraperitoneally (30 mg/kg) 24 h before IM. Intestinal transit was assessed 24 h postoperatively using fluorescent imaging 90 min after fluorescein gavaging (geometric centre [GC] of intestinal fluorescein progression). The small intestine was divided in 6 equal parts; mucosa-free muscularis segments were prepared and stored at -80° C for later analysis of myeloperoxidase (MPO) activity as an index of leukocyte infiltration, of the inflammatory cytokine interleukin 6 (IL-6) and of HO-1 protein expression. IL-6 and HO-1 were assayed by enzyme immunoassay and MPO by spectrophotometric monitoring.
Results Pre-treatment with DMF via both oral (GC: 7.4 ± 0.4; mean ± s.e.m. of n = 6) and intraperitoneal (GC: 7.7 ± 0.9) administration prevented the delayed transit seen after IM (GC: 4.6 ± 0.7; in controls 7.5 ± 0.3). Concomitantly peroral and intraperitoneal DMF significantly reduced the increased IL-6 levels in the intestinal muscularis caused by POI. However, it only reduced the elevated leukocyte infiltration (MPO) significantly when administered intraperitoneally. Furthermore, IM per se caused a significant increase in intestinal HO-1 protein expression as previously shown; this effect was not magnified by pre-treatment with DMF. Likewise, 12 h and 24 h after administration of DMF in non-operated animals, no increase in HO-1 levels was measured.
Conclusions The present study indicates that pre-treatment with DMF prevents delayed intestinal transit and reduces inflammation upon IM independently of intestinal HO-1 induction. To further investigate the possible mechanism of action of DMF in POI, the role of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element signaling pathway and of the Nrf2-independent inhibition of the proinflammatory NF-kappaB pathway will be studied.
