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OBJECTIVE The aim: This study was undertaken to investigatethe possible lung protective potential effect of zileuton during polymicrobial sepsis, through modulation of inflammatory and oxidative stress pathway. PATIENTS AND METHODS Materials and methods: 24 adult male Swiss-albino mice aged 8-12 weeks, with a weight of 25-35g, were randomized into 4 equal groups n=6, sham (laparotomy without CLP), CLP (laparotomy with CLP), vehicle (equivalent volume of DMSO 1 hour prior to CLP), and Zileuton (5 mg/kg 1 hour prior to CLP) group. After 24 hrs. of sepsis, the lung tissue harvested and used to assess IL-6, IL-1B, IL-17, LTB-4,12(S) HETE and F2-isoprostane as well as histological examination. RESULTS Results: Lung tissue inflammatory mediators IL-6, IL-1B, IL-17, LTB, 12 (S) HETE) and oxidative stress were carried out via ELISA. Lung tissue levels of IL-6, IL-1B, IL-17, LTB4, 12(S) HETE and oxidative stress (F2 isoprostan)level were significantly higher in sepsis group (p<0.05) as compared with sham group, while zileuton combination showed significant (p<0.05) lower level in these inflammatory mediators and oxidative stress as comparedto sepsis group. Histologically, All mice in sepsis group showed a significant (p<0.05) lung tissue injury, while in zileuton pretreated group showed significantly (p<0.05) reduced lung tissue injury. CONCLUSION Conclusions: The results of the present study revealed that zileuton has the ability to attenuate lung dysfunction during CLP induced polymicrobial sepsis in male mice through their modulating effects on LTB4,12(S) HETE and oxidative stress downstream signaling pathways and subsequently decreased lungtissue levelsof proinflammatory cytokines (IL-1β, and IL-6,IL-17).