Treatment with the 5-LOX antagonist Zileuton protects mice from postoperative ileus.

Introduction Previous work of our group showed that lipoxygenase (LOX) pathways become activated upon surgical manipulation of the bowel wall and revealed a beneficial immune modulating role of the LOX-derived anti-inflammatory mediator protectin DX in POI. While we found a particular role of 12/15-LOX in the anti-inflammatory LOX action during postoperative ileus (POI), the role of 5-LOX, which produces the proinflammatory leukotriene B4 (LTB4), remained unknown. The purpose of this study was to investigate the role of 5-LOX within the pathogenesis of POI in a mouse model. Methods POI was induced by intestinal manipulation (IM) of the small bowel in C57BL/6, 5-LOX-/- and CX3CR1GFP/+. Mice were either treated with a vehicle or with the synthetic 5-LOX antagonist Zileuton or were left untreated. Cellular localization of 5-LOX and LTB4 release were visualized by immunofluorescence or ELISA, respectively. POI severity was quantified by gastrointestinal transit (GIT) and leukocyte extravasation into the muscularis externa (ME) by immunohistochemistry. Results 5-LOX expression was detected 24h after IM within infiltrating leukocytes in the ME. LTB4 levels increased during POI in wildtype but not in 5-LOX-/- after IM. POI was ameliorated in 5-LOX-/- as shown by decreased leukocyte numbers and normalized GIT. Zileuton normalized the postoperative GIT and reduced the numbers of infiltrating leukocytes into the ME. Discussion/Conclusion Our data demonstrate that 5-LOX and its metabolite LTB4 play a crucial role in POI. Genetic deficiency of 5-LOX and pharmacological antagonism by Zileuton protected mice from POI. 5-LOX antagonism might be a promising target for prevention of POI in surgical patients.