NITROSYLATED-OLEIC ACID AMELIORATES POSTOPERATIVE ILEUS
Elizabeth Dyer*, Katherine O. Jones, Nicholas G. Minner, Anthony J. Bauer
Liberty University College of Osteopathic Medicine, Liberty University College of Osteopathic Medicine, Lynchburg, VA, US, academic/medsch, Lynchburg, VA
Background. Postoperative ileus (POI) is an iatrogenic condition, in which surgery triggers both neurogenic and inflammatory processes that result in impaired gastrointestinal motility. Overall, POI results in extended hospital stays at an estimated cost of $1.5 billion annually in the USA. Nitrosylated-fatty acids (NO2-FA) have been studied to treat inflammatory diseases. Acting as an electrophile, NO2-FAs inhibit pro-inflammatory nuclear factor kappa B and activate antioxidant nuclear factor erythroid 2-related factor 2 to decrease inflammation. Our objective was to determine the therapeutic potential of nitrosylated-oleic acid (NO2-OA) to ameliorate POI.
Methods. A standardized POI mouse model utilizing non-traumatic intestinal manipulation (IM) was used, which mimics the clinical procedure of "running the bowel". NO2-OA (7.5 mg/kg) was administered by intraperitoneal injection as a pretreatment at -6 and -3-hour and post-treatment at +3-hours relative to surgery. Twenty-four hours after surgery, gastrointestinal transit was assessed by orally feeding a non-digestible/non-absorbable marker (FITC-dextran 70kD) and plotting intestinal distribution histograms and calculating the geometric center (GC). Neutrophil transmigration into muscularis externa was quantified using a Hank-Yates myeloperoxidase stain. In vitro smooth muscle contractility was measured in jejunal circular muscle strips. Bethanechol was applied to the strips generating a dose response curve to analyze the effects of POI on smooth muscle contractility. (N=3-6, p<0.05)
Results. Transit showed a marked postoperative improvement with NO2-OA compared to the saline group. Alone NO2-OA did not alter transit compared to na├»ve saline controls (GC=10.2'▒0.73 vs. 9.8'▒0.86, respectively). As previously shown, IM resulted in a significant postoperative transit delay with the fluorescence localized to the proximal jejunum (GC=4.3'▒0.52, p>0.05). In contrast, NO2-OA treated mice undergoing IM significantly prevented the development of postoperative ileus (GC=8.6'▒0.69). Transit improvement appeared to be due to the anti-inflammatory effects of NO2-OA, because neutrophil extravasation into the muscularis whole-mounts was significantly prevented by NO2-OA (optical quantification of myeloperoxidase stained activity: control=0.001'▒0.00015, NO2-OA=0.002'▒0.00025, saline+IM=19.7'▒3.80 and NO2-OA+IM=3.88'▒0.042% of optical field, p<0.05). Postoperative bethanechol induced in vitro muscle contractions were also improved in NO2-OA treated mice compared to saline treatment. The effects of NO2-OA on molecular inflammatory mediators are current being assessed.
Conclusion. Overall, mice treated with NO2OA had improved postoperative transit, more robust muscle contractility, and decreased leukocytic infiltrates. Therefore, NO2-OA may be a promising therapeutic for the prevention of postoperative ileus.
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