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LUNG PROTECTIVE POTENTIAL EFFECT OF ZILEUTON DURING ENDOTOXAEMIA MODEL IN MALE MICE
Zainab Ali Alnfakh1, Rana Talib Al-Nafakh1, Ahmed M Abdul Hameed2
1DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS, FACULTY OF MEDICINE, UNIVERSITY OF KUFA, NAJAF, IRAQ.
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).
Insights
Zileuton demonstrated lung protective effects in a mouse model of polymicrobial sepsis. This drug reduced inflammatory mediators and oxidative stress, mitigating lung injury.
Area of Science:
- Sepsis research
- Pulmonary medicine
- Pharmacology
Background:
- Polymicrobial sepsis can lead to severe lung injury.
- Inflammatory and oxidative stress pathways are implicated in sepsis-induced lung damage.
Purpose of the Study:
- To investigate the lung protective potential of zileuton in polymicrobial sepsis.
- To assess zileuton's modulation of inflammatory and oxidative stress pathways in the lungs.
Main Methods:
- Adult male Swiss-albino mice underwent cecal ligation and puncture (CLP) to induce sepsis.
- Mice were randomized into sham, CLP, vehicle, and zileuton treatment groups.
- Lung tissues were analyzed for inflammatory cytokines (IL-6, IL-1β, IL-17), leukotrienes (LTB4), HETEs, and oxidative stress markers (F2-isoprostane).
Main Results:
- Sepsis significantly increased lung inflammatory mediators and oxidative stress markers compared to sham.
- Zileuton treatment significantly reduced these inflammatory mediators and oxidative stress markers.
- Histological examination revealed significant lung tissue injury in the sepsis group, which was reduced by zileuton pretreatment.
Conclusions:
- Zileuton attenuates lung dysfunction in polymicrobial sepsis.
- The protective effect is mediated by modulating LTB4, 12(S) HETE, and oxidative stress pathways.
- Zileuton decreases pro-inflammatory cytokine levels (IL-1β, IL-6, IL-17) in sepsis-induced lung injury.
