title: A role for 12/15-lipoxygenase-derived proresolving mediators in postoperative ileus: protectin DX-regulated neutrophil extravasation.
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.
authors: Departments of *Surgery and Cardiac Surgery, University of Bonn, Bonn, Germany; and Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Kathy
authors: K
authors: Stein
authors: Departments of *Surgery and Cardiac Surgery, University of Bonn, Bonn, Germany; and Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Melissa
authors: M
authors: Stoffels
authors: Departments of *Surgery and Cardiac Surgery, University of Bonn, Bonn, Germany; and Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Mariola
authors: M
authors: Lysson
authors: Departments of *Surgery and Cardiac Surgery, University of Bonn, Bonn, Germany; and Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Bianca
authors: B
authors: Schneiker
authors: Departments of *Surgery and Cardiac Surgery, University of Bonn, Bonn, Germany; and Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Oliver
authors: O
authors: Dewald
authors: Departments of *Surgery and Cardiac Surgery, University of Bonn, Bonn, Germany; and Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Gerhard
authors: G
authors: Krönke
authors: Departments of *Surgery and Cardiac Surgery, University of Bonn, Bonn, Germany; and Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors: Jörg C
authors: JC
authors: Kalff
authors: Departments of *Surgery and Cardiac Surgery, University of Bonn, Bonn, Germany; and Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nürnberg, Erlangen, Germany sven.wehner@ukb.uni-bonn.de.
authors: Sven
authors: S
authors: Wehner
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D004281:Docosahexaenoic Acids / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004655:Emulsions; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000627:therapeutic use; D005769:Gastrointestinal Motility / Q000187:drug effects; D045823:Ileus / Q000201:enzymology / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D007249:Inflammation; D007583:Jejunum / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009130:Muscle, Smooth / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000276:immunology*; D011183:Postoperative Complications / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control; D013047:Specific Pathogen-Free Organisms
chemical_list: C000591716:10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid; D004655:Emulsions; D015525:Fatty Acids, Omega-3; C545423:resolvin D2; D004281:Docosahexaenoic Acids; C062894:17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: lipid; monocytes; resolution