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

Abstract

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.

Rapid screening and isolation of 5‐lipoxygenase inhibitors in Inonotus obliquus and mechanism of action in the treatment of asthma

“…5-LOX catalyzes the production of cysteine leukotrienes from arachidonic acid, causing airway smooth muscle contraction, increased airway mucus secretion, mucosal edema, and inflammatory cell aggregation thus inducing asthma [9,10]. The only 5-LOX inhibitor currently on the market is Zileuton, which has been shown to improve asthma in clinical studies, but it has the side effect of causing damage to liver function and may lead to potential cardiovascular disease [11,12]. It was found that herbal medicines are rich in natural 5-LOX inhibitors, mainly flavonoids or polyphenols, pentacyclic triterpenoids, and alkaloids.…”