A role for 12/15-lipoxygenase-derived proresolving mediators in postoperative ileus: protectin DX-regulated neutrophil extravasation. Issue 2 (20th August 2015)

• Record Type: Journal Article
• Authors: Stein, Kathy; Stoffels, Melissa; Lysson, Mariola; Schneiker, Bianca; Dewald, Oliver; Krönke, Gerhard; Kalff, Jörg C; Wehner, Sven
• Is Part Of: Journal of leukocyte biology. Volume 99:Issue 2(2016)
• Page Start: 231
• Page End: 239
• Publication Date: 2015-08-20
• Subjects: monocytes -- lipid -- resolution; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.3HI0515-189R
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : Resolution of POI involves monocytotic 12/15-LOX activity and generation of PDX, resulting in reduction of neutrophil infiltration into the postoperative bowel wall. Abstract: Resolution of inflammation is an active counter-regulatory mechanism involving polyunsaturated fatty acid-derived proresolving lipid mediators. Postoperative intestinal motility disturbances, clinically known as postoperative ileus, occur frequently after abdominal surgery and are mediated by a complex inflammation of the intestinal muscularis externa. Herein, we tested the hypothesis that proresolving lipid mediators are involved in the resolution of postoperative ileus. In a standardized experimental model of postoperative ileus, we detected strong expression of 12/15-lipoxygenase within the postoperative muscularis externa of C57BL/6 mice, predominately located within CX3CR1 + /Ly6C + infiltrating monocytes rather than Ly6G + neutrophils. Mass spectrometry analyses demonstrated that a 12/15-lipoxygenase increase was accompanied by production of docosahexaenoic acid-derived lipid mediators, particularly protectin DX and resolvin D2, and their common precursor 17-hydroxy docosahexaenoic acid. Perioperative administration of protectin DX, but not resolvin D2 diminished blood-derived leukocyte infiltration into the surgically manipulated muscularis externa and improved the gastrointestinal motility. Flow cytometry analyses showed impaired Ly6G + /Ly6C + neutrophil extravasation after protectin DX treatment, whereas Ly6G - /Ly6C + monocyte numbers were not affected. 12/15-lipoxygenase-deficient mice, lacking endogenous protectin DX synthesis, demonstrated increased postoperative leukocyte levels. Preoperative intravenous administration of a docosahexaenoic acid-rich lipid emulsion reduced postoperative leukocyte infiltration in wild-type mice but failed in 12/15-lipoxygenase-deficient mice mice. Protectin DX application reduced leukocyte influx and rescued 12/15-lipoxygenase-deficient mice mice from postoperative ileus. In conclusion, our results show that 12/15-lipoxygenase mediates postoperative ileus resolution via production of proresolving docosahexaenoic acid-derived protectin DX. Perioperative, parenteral protectin DX or docosahexaenoic acid supplementation, as well as modulation of the 12/15-lipoxygenase pathway, may be instrumental in prevention of postoperative ileus.