Protective effect of exogenous nitrite in postoperative ileus

Abstract

BACKGROUND AND PURPOSEAs the pathogenesis of postoperative ileus (POI) involves inflammation and oxidative stress, comparable to ischaemia/reperfusion injury which can be ameliorated with nitrite, we investigated whether nitrite can protect against POI and explored the mechanisms involved. EXPERIMENTAL APPROACHWe used intestinal manipulation (IM) of the small intestine to induce POI in C57BL/6J mice. Sodium nitrite (48 nmol) was administered intravenously just before IM. Intestinal transit was assessed using fluorescent imaging. Bethanechol-stimulated jejunal circular muscle contractions were measured in organ baths. Inflammatory parameters, neutrophil infiltration, inducible NOS (iNOS) activity, reactive oxygen species (ROS) levels, mitochondrial complex I activity and cGMP were measured in the intestinal muscularis. KEY RESULTSPre-treatment with nitrite markedly improved the delay in intestinal transit and restored the reduced intestinal contractility observed 24 h following IM. This was accompanied by reduced protein levels of TNF-α, IL-6 and the chemokine CCL2, along with reduced iNOS activity and ROS levels. The associated neutrophil influx at 24 h was not influenced by nitrite. IM reduced mitochondrial complex I activity and cGMP levels; treatment with nitrite increased cGMP levels. Pre-treatment with the NO scavenger carboxy-PTIO or the soluble guanylyl cyclase inhibitor ODQ abolished nitrite-induced protective effects. CONCLUSIONS AND IMPLICATIONSExogenous nitrite deserves further investigation as a possible treatment for POI. Nitrite-induced protection of POI in mice was dependent on NO and this effect was not related to inhibition of mitochondrial complex I, but did involve activation of soluble guanylyl cyclase.

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

“…This local molecular inflammatory response is followed by a cellular inflammatory phase with the recruitment of circulatory leukocytes into the muscularis and subsequent release of more pro‐inflammatory mediators . As reported previously for the murine model of POI, the inflammatory response when manipulating the murine small intestine was also confirmed in the present study. When measured at 3, 6, and 24 hours after IM, the influx of neutrophils progressively increased with the highest value at 24 hours while the intestinal level of the inflammatory cytokine IL‐6 peaked already at 3 hours after manipulation and then decreased, still being significantly enhanced at 24 hours.…”

“…When measured at 3, 6, and 24 hours after IM, the influx of neutrophils progressively increased with the highest value at 24 hours while the intestinal level of the inflammatory cytokine IL‐6 peaked already at 3 hours after manipulation and then decreased, still being significantly enhanced at 24 hours. The same time‐dependent induction pattern of IL‐6 protein/mRNA expression and MPO activity after IM is observed in other studies …”

“…15,16 This local molecular inflammatory response is followed by a cellular inflammatory phase with the recruitment of circulatory leukocytes into the muscularis and subsequent release of more pro-inflammatory mediators. 43 As reported previously for the murine model of POI, 19,21,44 the inflammatory response when manipulating the murine small intestine was also confirmed in the present study. When measured at protein/mRNA expression and MPO activity after IM is observed in other studies.…”

“…When measured at protein/mRNA expression and MPO activity after IM is observed in other studies. 19,41,44 Because of the importance of the inflammatory cascade in the pathogenesis of POI, it has become the primary target in the development of novel treatment options for POI. Induction of HO-1, the enzyme producing CO and biliverdin/bilirubin, with hemin has been shown to reduce inflammation in different body systems in a variety of animal models.…”

Disruption of the pacemaker activity of interstitial cells of Cajal via nitric oxide contributes to postoperative ileus

“…On the other hand, we previously suggested that NO‐mediated oxidative stress rather than the cGMP pathway could decrease c‐Kit‐positive ICC networks during inflammatory condition. Some reports have indicated that oxidative stress participates in POI . We found that lower concentration of NO donor inhibited pacemaker activity but did not disrupt c‐Kit‐positive ICC network.…”