Abstract
Objective: Intestinal inflammation triggers postoperative ileus (POI), commonly seen after abdominal surgery and characterized by impaired gastrointestinal transit; when prolonged, this leads to increased morbidity. Hydrogen sulfide (H2S) is recognized as an important mediator of many (patho)physiological processes, including inflammation, and is now investigated for anti-inflammatory application. Therefore, the aim of this study was to investigate the effect of the H2S-releasing naproxen derivative ATB-346, developed to reduce gastrointestinal injury by naproxen, and the slow-release H2S donor GYY4137 on intestinal inflammation and delayed gastrointestinal transit in murine POI.Methods: C57Bl6J mice were fasted for 6 h, anesthetized and after laparotomy, POI was induced by compressing the small intestine with two cotton applicators for 5 min (intestinal manipulation; IM). GYY4137 (50 mg/kg, intraperitoneally), ATB-346 (16 mg/kg, intragastrically) or naproxen (10 mg/kg, intragastrically) were administered 1 h before IM. At 24 h postoperatively, gastrointestinal transit was assessed via fluorescent imaging, and mucosa-free muscularis segments were prepared for later analysis. Inflammatory parameters and activity of inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2 were measured. Histological examination of whole tissue sections was done on hematoxylin-eosin stained slides.Results: Pre-treatment with GYY4137 (geometric center; GC: 7.6 ± 0.5) and ATB-346 (GC: 8.4 ± 0.3) prevented the delayed transit induced by IM (GC: 3.6 ± 0.5 vs. 9.0 ± 0.4 in non-operated controls) while naproxen only partially did (GC: 5.9 ± 0.5; n = 8 for all groups). GYY4137 and ATB-346 significantly reduced the IM-induced increase in muscular myeloperoxidase (MPO) activity and protein levels of interleukin (IL)-6, IL-1β and monocyte chemotactic protein 1; the reduction by naproxen was less pronounced and only reached significance for MPO activity and IL-6 levels. All treatments significantly reduced the increase in COX-2 activity caused by IM, whereas only GYY4137 significantly reduced the increase in iNOS activity. Naproxen treatment caused significant histological damage of intestinal villi. Conclusion: The study shows that naproxen partially prevents POI, probably through its inhibitory effect on COX-2 activity. Both ATB-346 and GYY4137 were more effective, the result with GYY4137 showing that H2S per se can prevent POI.
Highlights
Postoperative ileus (POI) refers to the transient impairment of gastrointestinal motility, which commonly occurs after abdominal surgery
In mice that underwent intestinal manipulation, fluorescein-labeled dextran was mostly present in the proximal part of the small bowel, pointing out a delay in transit (Figure 2B), which was confirmed by a significant reduction in Geometric center (GC) (Figure 2F)
Pre-treatment with 50 mg/kg GYY4137 i.p. or 16 mg/kg ATB-346 i.g. reduced the delay in transit caused by intestinal manipulation (IM), as indicated by the shift of fluorescein-labeled dextran to the distal part of the small bowel (Figures 2C–E); the GC was significantly increased vs. that in untreated manipulated animals and no longer significantly different from that in non-manipulated control mice (Figure 2F)
Summary
Postoperative ileus (POI) refers to the transient impairment of gastrointestinal motility, which commonly occurs after abdominal surgery. It presents clinically as abdominal distension, inability to tolerate an oral diet, absence of bowel sounds and lack of flatus and defecation. It resolves within 3 days, but when prolonged, nausea and vomiting will further contribute to increased morbidity, length of hospital stay and increased healthcare costs (Boeckxstaens and De Jonge, 2009). There is need for new treatment options, especially those targeting the intestinal inflammation (Van Bree et al, 2012)
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