Treatment with the 5-Lipoxygenase Antagonist Zileuton Protects Mice from Postoperative Ileus.

Jana Enderes, Shilpashree Mallesh, Kathy Stein, Melissa Wagner, Mariola Lysson, Bianca Schneiker, Joerg C Kalff, Sven Wehner

European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes 2022

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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 postoperative ileus (POI). While we found a particular role of 12/15-LOX in the anti-inflammatory LOX action during POI, the role of 5-LOX, which produces the pro-inflammatory 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. 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. 5-LOX expression was detected 24 h after IM within infiltrating leukocytes in the ME. LTB4 levels increased during POI in wild type 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. 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. © 2022 S. Karger AG, Basel.

Citation

Jana Enderes, Shilpashree Mallesh, Kathy Stein, Melissa Wagner, Mariola Lysson, Bianca Schneiker, Joerg C Kalff, Sven Wehner. Treatment with the 5-Lipoxygenase Antagonist Zileuton Protects Mice from Postoperative Ileus. European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes. 2022;63(4):224-231