ABSTRACT
Objective o investigate the prophylactic and therapeutic effects of montelukast,a cysteinyl leukotriene receptor-1 (CysLT1R) antagonist,on the delayed neuropsychological sequelae (DNS) in rat model of carbon monoxide (CO) poisoning and to explore the possible underlying mechanism.Methods A total of 90 rats were acclimated for one week prior to screening rat by Morris water maze test.Ten rats were randomly assigned to control group (Con group),and the remaining 80 rats were subjected to modified method of intraperitoneal injection of CO gas to establish animal model of acute CO poisoning,Thereafter,the survival rats randomized into CO poisoning group (Mod group),low-dose montelukast group (ML group),medium-dose montelukast group (MM group),high-dose montelukast group (MH group) (n =10 each).Montelukast was accordingly administered via intragastric tube at different intervals (30 min,4 h and 12 h) after CO poisoning,and then montelukast was administered every 12 hours for 7 consecutive days.The rats of control group and Mod group received equal volume of normal saline instead at given intervals.Twenty-one days after CO exposure,the average escape latency was measured by Morris water maze test to screen DNS rats followed by H-E staining to observe the pathological changes of cortex and hippocampal CA1 region and TUNEL was used to assess the apoptosis of neurons in cortex and hippocampal CA1 region after rats sacrificed.Results All CO-exposed rats exhibited cognition function lowered,and the escape latency (seconds) in Mod group (43.3 ± 15.5),ML group (31.5 ± 13.2) and MH groups (30.1 ± 12.2) was significantly prolonged compared with Con group (12.1 ± 3.0) (P ＜ 0.05),whereas the difference between MM group (15.0 ± 6.6) and Con group was statistically insignificant (P ＞ 0.05).Compared with Mod group,the escape latency in montelukast treatment groups was shortened,whereas the significant difference in escape latency only found between Mod group and MM group (P ＜ 0.05).Except for Con group,DNS was evident in CO-exposed groups,and the numbers of DNS rats in Mod,ML,MM and MH groups were 8,5,1,4,respectively,which made statistically significant differences to Con group (P ＜ 0.05) except MM group.The DNS incidence in MM group was lower than that in Mod group (P ＜ 0.05).Mod group exhibited severe histopathological injury to the brain,with evident apoptosis of neural cells,whereas in the groups with montelukast treatment,histopathological damage to the brain was mitigated and the number of apoptotic neuronal cells was diminished noticeably in MM group.Conclusion Montelukast can ameliorate the cognitive function of rats,decrease the incidence of DNS and reduce the apoptosis of neural cells as well as attenuate neuronal cell injury,thus exerting neuroprotection against DNS in rats with CO poisoning.
ABSTRACT
Objective To explore whether TNF-α involves in the modulation of Cysteinyl leukotriene receptor 1 (CysLT1) expression in bronchial epithelial cells.Methods The bronchial epithelial cell lines 16HBE cells were stimulated with different concentration (0.00,0.05,0.50,5.00,20.00 μg/L) of TNF-α for 48 hours,and CysLT1 mRNA in 16HBE cells was measured by reverse transcription(RT)-PCR.CysLT1 expression was detected by immunohistochemistry.Results 16HBE cells did not express CysLT1,after the cells were treated with TNF-α,obvious expression of CysLT1 were detected by immunohistochemistry.The weak CysLT1 mRNA expression was observed by RT-PCR in 16HBE cells,and after the cells were treated with TNF-α for 48 hours,CysLT1 mRNA expression were upregulated.When the concentrations of TNF-α were 0.00,0.05,0.50,5.00,and 20.00 μg/L respectively,the relative intensities of CysLT1 mRNA/β-actin were 0.048,0.105,0.177,0.182,0.495,respectively.Conclusions TNF-α can upregulate CysLT1 mRNA expression in 16HBE ceils in a dose-dependent manner.When infected by virus,respiratory tract produces abundant TNF-α.The TNF-α can upregulate the expression of CysLT1 in epithelial cells,enhance inflammation reaction in respiratory tract.This may explain partially the mechanism of exacerbation of asthma induced by respiratory tract infection.
ABSTRACT
PURPOSE: Cysteinyl leukotrienes are important proinflammatory mediators in asthma. Recently, it was suggested that a promoter polymorphism in the genes encoding for leukotriene C4 synthase (LTC4S), a key enzyme in the leukotriene synthetic pathway, and cysteinyl leukotriene receptor 1 (CysLTR1) might be associated with aspirin-intolerant asthma. We investigated whether polymorphisms in LTC4S and CysLTR1 genes or their interactions were associated with the asthma phenotype, lung function, or bronchial hyperreactivity (BHR) in Korean children. METHODS: A total of 856 asthmatic children and 254 non-asthmatic controls were enrolled; a skin prick test, lung function test and bronchial provocation test were performed. Of those enrolled, 395 children underwent exercise challenge tests. The LTC4S A(-444)C and CysLTR1 T(+927)C were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Of those enrolled, 699 children were classified as having atopic asthma and 277 children, as having exercise-induced asthma (EIA). LTC4S and CysLTR1 polymorphisms were not associated with atopic asthma, EIA, or asthma per se. Lung function and BHR were not significantly different between the wild type (AA or TT) and the variant (AC+CC or TC+CC) genotypes in asthmatics, atopic asthmatics, and EIA (+) asthmatics, while total eosinophil counts were higher in the variant type of LTC4S than in the wild type in atopic asthmatics. There were no associations between the gene-gene interactions of LTC4S and CysLTR1 genotypes and the asthma phenotypes. CONCLUSION: LTC4S A(-444)C and CysLTR1 T(+927)C polymorphisms and their gene-gene interactions are not associated with asthma phenotype, lung function, or BHR in Korean children.