NO donor V-PYRRO/NO inhibits expression of leukotriene C4 synthase in early stage of hepatic ischemia/reperfusion injury in rats / 基础医学与临床

Objective To explore the mechanism underlying a selective liver nitric oxide donor V-PYRRO/NO effects on the gene expression of LTC4 synthase(LTC4S) during hepatic ischemia reperfusion(I/R).Methods Adult male SD rats were divided into 3 groups:control group(sham),ischemic-reperfusion group(I/R) and V-PYRRO/NO group. Liver subjected to 1 hour of partial hepatic ischemia followed by 5 hours of reperfusion, saline or V-PYRRO/NO[1.06 mmol/(kg·h)] administered intravenously. The mRNA expression of LTC4S in rat liver was examined by RT-PCR method,the protein expressions of NF-κB p65,p50 and IκB in liver cell lysates and nu-clear extracts were detected by Western blot analysis. Results Hepatic mRNA expression of LTC4S in I/R group was higher than that in sham group(P<0.05), whereas it was lower in V-PYRRO/NO group than that in I/R group(P<0.05). Moreover,compared with sham group,the protein expressions of NF-κB p65 and p50 in nucleus extract were markedly increased(P<0.01) but significantly decreased in cytoplasm(P<0.01) in I/R group. V-PYRRO/NO reversed completely the increase of these protein expressions in nucleus extract (P<0.05) and the decrease of them in cytoplasm(P<0.01,P<0.05) during hepatic I/R injury.However,IκB protein in three groups did not change. Immunohistochemistry staining revealed that no marked positive staining for NF-κB p65 was found in sham liver,I/R liver exhibited strong cytoplasmic and nuclear positive staining for NF-κB p65,but V-PYRRO/NO I/R group liver presented slight cytoplasmic and nuclear staining. Conclusions V-PYRRO/NO may down-regulate LTC4S mRNA expression by inhibiting NF-κB activation independent of IκB during hepatic I/R injury.

The relationship between LTC4S, ALOX5 genetic polymorphism and clinical efficacy of leukotriene receptor modula-tors in children with asthma / 临床儿科杂志

Objective To study the effect of genetic polymorphism of leukotriene C4 synthase (LTC4S) and 5-lipoxy-genase (ALOX5) on efifcacy of leukotriene receptor antagonist (LTRA) in children with moderate persistent asthma. Methods Seventy-two children with moderate persistent asthma who visited the out-patient clinic of Shanghai Children’s Medical. Center from June 2011 to June 2013 were divided into two groups, each of which ifrst had ICS or LTRA+ICS for twelve weeks and then had the other for another twelve weeks. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to assess the genetic polymorphism of LTC4S RS730012 and ALOX5 RS2115819. Pulmonary function, clinical symptoms and C-ACT score were evaluated before and after treatment. Results After the treatment with LTRA, 75%forced expiratory lfow (FEF75) was improved more signiifcantly in patients with A/C or C/C genotype at LTC4S (RS730012) locus than in patients with A/A genotype. After the treatment with LTRA+ICS, there was no difference of pulmonary function among patients with different genotypes at ALOX5 (RS2115819). Conclusions The SNP of LTC4S (RS730012) is associated with the efifcacy of montelukast in asthmatic patients because of the improvement of small airway function.

Association study of polymorphism in leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes with phenotype of asthma and clinical parameters in Korean children / 소아과

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.

Association of Leukotriene C4 Synthase Gene Polymorphism with Clinical Response to Montelukast in Childhood Asthma / 소아과

PURPOSE: Cysteinyl leukotrienes are important inflammatory mediators in the pathogenesis of asthma; therefore interruption of cysteinyl leukotrienes by leukotriene receptor antagonists improves clinical symptoms in the management of patients with mild to moderate asthma. We evaluated whether clinical response to montelukast, a leukotriene receptor antagonist, in childhood asthma was predicted by genotypes of leukotriene C4 synthase (LTC4S) promoter gene polymorphism. METHODS: An 8-week prospective, open trial of montelukast was carried out in 161 children with mild to moderate asthma. Genotyping of LTC4S gene polymorphism was determined by restriction fragment length polymorphism. RESULTS: The distribution of the LTC4S genotypes AA, AC, and CC was 70.8 percent, 23.6 percent, and 5.6 percent, respectively in asthma group and 74.0 percent, 22.6 percent, and 3.4 percent, respectively in control group. A statistically significant difference in the distribution of LTC4S genotype was not observed between the asthma and the control groups, and there was no significant difference between the LTC4S genotype and asthma severity. The responders to montelukast were significantly prevalent in the mild asthma group (P< 0.05). There was no significant difference in the distribution of the responders compared to non-responders within genotype in the total asthma group or the moderate asthma group. However, the responsiveness for montelukast was significant difference within genotype for both AA and AC/CC in the mild asthma group: The AA genotype was more included in the responder group (P< 0.05). CONCLUSION: In the mild persistent asthma group, the A allele of LTC4S polymorphism may be regarded as a predictable factor for clinical response to montelukast. However, LTC4S polymorphism was not significantly associated with the clinical response to montelukast in asthmatic children.