Alnfakh Zainab Ali, Al-Nafakh Rana Talib, Hameed Ahmed M Abdul, Abdelhussain Mohamad Abid, Hadi Najah R
DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS, FACULTY OF MEDICINE, UNIVERSITY OF KUFA, NAJAF, IRAQ.
DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS, FACULTY OF MEDICINE, JABIR IBN HAYYAN MEDICAL UNIVERSITY, AL NAJAF AL-ASHRAF, IRAQ.
Wiad Lek. 2022;75(12):3066-3073. doi: 10.36740/WLek202212130.
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.
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: 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.
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).
本研究旨在通过调节炎症和氧化应激途径，探讨齐留通在多微生物脓毒症期间可能的肺保护潜在作用。
24只8 - 12周龄、体重25 - 35克的成年雄性瑞士白化小鼠，随机分为4组，每组n = 6只，分别为假手术组（开腹但不进行盲肠结扎穿孔术）、盲肠结扎穿孔术组（开腹并进行盲肠结扎穿孔术）、溶剂对照组（在盲肠结扎穿孔术前1小时给予等量二甲基亚砜）和齐留通组（在盲肠结扎穿孔术前1小时给予5毫克/千克齐留通）。脓毒症24小时后，采集肺组织，用于评估白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）、白细胞介素-17、白三烯B4（LTB-4）、12（S）-羟基二十碳四烯酸（12(S) HETE）和F2 -异前列腺素，以及进行组织学检查。
通过酶联免疫吸附测定法检测肺组织炎症介质IL-6、IL-1β、IL-17、白三烯B4（LTB4）、12（S）-羟基二十碳四烯酸（12(S) HETE）和氧化应激。与假手术组相比，脓毒症组肺组织中IL-6、IL-1β、IL-17、LTB4、12（S）-羟基二十碳四烯酸（12(S) HETE）水平和氧化应激（F2 -异前列腺素）水平显著更高（p < 0.05），而与脓毒症组相比，齐留通联合组这些炎症介质和氧化应激水平显著更低（p < 0.05）。组织学检查显示，脓毒症组所有小鼠均表现出显著的（p < 0.05）肺组织损伤，而齐留通预处理组肺组织损伤显著减轻（p < 0.05）。
本研究结果表明，齐留通能够减轻盲肠结扎穿孔术诱导的雄性小鼠多微生物脓毒症期间的肺功能障碍，其机制是通过调节白三烯B4（LTB4）、1十二（S）-羟基二十碳四烯酸（12(S) HETE）和氧化应激下游信号通路，进而降低肺组织中促炎细胞因子（IL-1β、IL-6、IL-17）水平。
