A role for 12/15-lipoxygenase-derived proresolving mediators in postoperative ileus: protectin DX-regulated neutrophil extravasation

J Leukoc Biol. 2016 Feb;99(2):231-9. doi: 10.1189/jlb.3HI0515-189R. Epub 2015 Aug 20.


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.

Keywords: lipid; monocytes; resolution.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / deficiency
  • Arachidonate 12-Lipoxygenase / physiology*
  • Arachidonate 15-Lipoxygenase / deficiency
  • Arachidonate 15-Lipoxygenase / physiology*
  • Chemotaxis, Leukocyte* / physiology
  • Docosahexaenoic Acids / biosynthesis
  • Docosahexaenoic Acids / deficiency
  • Docosahexaenoic Acids / physiology*
  • Docosahexaenoic Acids / therapeutic use
  • Drug Evaluation, Preclinical
  • Emulsions
  • Fatty Acids, Omega-3 / administration & dosage
  • Fatty Acids, Omega-3 / therapeutic use
  • Gastrointestinal Motility / drug effects
  • Ileus / enzymology
  • Ileus / etiology
  • Ileus / immunology*
  • Ileus / prevention & control
  • Inflammation
  • Jejunum / immunology*
  • Jejunum / metabolism
  • Jejunum / pathology
  • Mice
  • Mice, Inbred C57BL
  • Models, Immunological
  • Muscle, Smooth / immunology*
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / pathology
  • Neutrophils / immunology*
  • Postoperative Complications / enzymology
  • Postoperative Complications / immunology*
  • Postoperative Complications / prevention & control
  • Specific Pathogen-Free Organisms


  • 10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid
  • Emulsions
  • Fatty Acids, Omega-3
  • resolvin D2
  • Docosahexaenoic Acids
  • 17-hydroxy-4,7,10,13,15,19-docosahexaenoic acid
  • Alox15 protein, mouse
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase