2.Association of Leukotriene C4 Synthase Gene Polymorphism with Clinical Response to Montelukast in Childhood Asthma.
Korean Journal of Pediatrics 2005;48(7):766-771
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.
Alleles
;
Asthma*
;
Child
;
Genotype
;
Humans
;
Leukotriene Antagonists
;
Leukotriene C4*
;
Leukotrienes
;
Polymorphism, Restriction Fragment Length
;
Prospective Studies
;
Receptors, Leukotriene
3.Effect of theophylline on urinary leukotriene B4 and C4 excretion in children with asthma.
Hai Lee CHUNG ; Jung Jin LEE ; Sang Gyung KIM
Journal of Asthma, Allergy and Clinical Immunology 2000;20(5):710-716
BACKGROUND: Theophylline has been used in the treatment of asthma for decades as a broncho- dilator, but recent studies suggested that it has anti-inflammatory and immunomodulatory properties. OBJECTIVE: The aim of this study was to determine the effect of theophylline therapy on urinary excretion of leukotriene B4 (LTB4) and C4 (LTC4), which have been known to play a role in the airway inflammation in asthmatic patients. METHODS: Fifty-one patients, aged 13 months to 6 years, who were hospitalized with asthma were randomized in to 3 groups according to treatment regimen. Twenty-one patients were administered theophylline with budesonide and salbutamol inhalation (Group 1). Fifteen patients were treated with budesonide and salbutamol inhalation (Group 2) and the other fifteen patients with salbutamol inhalation only (Group 3). Urine samples for the determination of LTB4 and LTC4 were collected on admission and on the fifth hospital day in each patient. The concentrations of urinary leukotrienes were measured by ELISA (Neogen, U.S.A.) and corrected by urinary creatinine levels. Ten controls were also studied. RESULTS: The initial urinary LTC4 levels in asthmatic children were significantly higher than in controls. Urinary LTC4 was significantly decreased after treatment compared with the initial level in group 1 (p<0.05), but not in groups 2 and 3. Urinary LTB4 did not show significant difference between patients and controls on admission and showed no significant change after treatment compared with the initial levels in all three groups. CONCLUSION: These results suggest that the suppression of LTC4 synthesis is one of the anti-inflammatory mechanisms of theophylline and support the use of theophylline as a the rapeutic agent in asthmatic patients.
Albuterol
;
Asthma*
;
Budesonide
;
Child*
;
Creatinine
;
Enzyme-Linked Immunosorbent Assay
;
Humans
;
Inflammation
;
Inhalation
;
Leukotriene B4*
;
Leukotriene C4
;
Leukotrienes
;
Theophylline*
4.Antagonism of Sophoricoside from Sophorica japonica on IL-5.
Yuan Xi ZHE ; Youngsoo KIM ; Sang Hun JUNG ; Seung Ho LEE ; Jae Chun RYU ; Mi Kyeong KIM
Journal of Asthma, Allergy and Clinical Immunology 2003;23(3):459-466
BACKGROUND: Allergic disease is an inflammatory disease, whose main inflammatory cells are eosinophils, mast cells, and T lymphocytes. From that point, new therapeutic targets on allergic inflammation focusing on them are under investigation. We extracted four isoflavonoids from Sophorica japonica such as sophi, orobol, genistin, and genistein which has been known as PTK antagonist. We documented those three iso-flavonoids except genistein had an anti-inflammatory effect as potent as dexamethasone on carageen-induced ear model. Also they had antagonism on the Y-16 cell line, whose growth is dependent on IL-5. OBJECTIVES: From above results, in this experiment, we tried to find antagonistic effects of those compounds on IL-5 using the inhibition of eosinophil activation and survival in vitro and possibility of anti-allergic medicine. METHODS: LTC4 by RIA and ECP for degranulation by UniCAP(TM), which had been used previously were activation markers. RESULTS: Among those compounds, sophi was the most potent antagonist on IL-5 induced LTC4 release, degranulation, and survival. Orobol and genistin also had antagonism on them, but genistein, an antagonist of PTK didn't show any antagonistic effects. CONCLUSION: From these results, we concluded those three iso-flavonoids were IL-5 antagonist, and the mechanism of it might not be through PTK signaling.
Cell Line
;
Dexamethasone
;
Ear
;
Eosinophils
;
Genistein
;
Inflammation
;
Interleukin-5*
;
Leukotriene C4
;
Mast Cells
;
T-Lymphocytes
5.House dust mite dose not directly activate the human peripheral blood eosinophils in house dust mite-sensitized asthmatics.
Korean Journal of Allergy 1997;17(2):141-150
In asthma, eosinophil roles as main end inflammatory effector cell, but neither the activation process nor the stimuli of that is known clearly, yet. Even though allergic asthma is IgE-mediated type I hypersensitivity disease, it is not clear whether there is FcepsilonRI on the surface of eosinophil like mast cell or basophil which is activated through the FcepsilonRl bridging with sensitized allergens. In this study, we speculate if there's FcepsilonRI on the eosinophil, sensitized allergen activates it like mast cell in allergic asthmatics, and with this result we can find out one of the stimuli of eosinophil in asthma and can suggest the possibility of the existence of FcepsilonRI on the eosinophil. We did direct stimulation of the house dust mite -sensitized astknatics'purified peripheral blood normodense eoisnophils with Dermatophagoides pteronyssiuns. Then we measured the LTC4 and ECP from the supernatant by RIA kit and observed the morphological changes with electron microscopy. There was neither increase in LTC4 and ECP level nor the morphological changes in asthmatics. And there were no significant differences in both LTC4, and ECP level, and morphologic changes between asthmatics and controls. We would summerize that house dust mite dose not dirctly activate eosinophil from house dust mite-sensitized asthmatics and couldn't find out the possibility that there's FcepsilonRI on the surface of eoslnophils. But no exitstence of FcepsilonRI on the eosinophil is the indirect evidence, so from now on we try to find more direct evidence of that by blotting.
Allergens
;
Asthma
;
Basophils
;
Dust*
;
Eosinophils*
;
Humans*
;
Hypersensitivity, Immediate
;
Leukotriene C4
;
Mast Cells
;
Microscopy, Electron
;
Pyroglyphidae*
6.Interleukin-16 in asthma.
Jing-min DENG ; Huan-zhong SHI
Chinese Medical Journal 2006;119(12):1017-1025
7.Comparative study on the activation status of eosinophils in exerise- and allergen-induced asthma.
Young Yull KOH ; Jung Hwan CHOI ; Chan Hoo PARK ; Sun Young LEE ; Chang Keun KIM ; Jin Hwa JEONG
Korean Journal of Allergy 1997;17(3):286-298
Exercise is one of the most ubiquitous triggers of acute bouts of asthma. Late asthmatic responses(LARs) have been described following strenuous exercise, as in allergen-induced asthma. However, most studies have reported that airway responsiveness is not increased after exercise, even in subjects with LAR to exercise. This suggests that LAR after exercise may not be associated with inflammatory changes in the airways. We have frequently seen asthmatic children whose complaint is that symptoms are exacerbated at night after strenuous daytime exercise. Furthermore, airway responsiveness to allergen was reported to increase after LAR to exercise. Therefore, it is crucial to know whether exercise can induce airway inflammation, as in allergen-induced asthma. As an indirect measure to investigate it, we measured the activation status of eosinophil granulocyte in the peripheral blood during the early and late phase of exercise- or allergen-induced asthma. Eight subjects who showed early asthmatic response(EAR) and LAR(group 1), or EAR only (group 2) to allergen (Dermatophagoides pteronyssinus) challenge were selected. Similarly eight subjects who showed EAR and LAR(group 3), or EAR only (group 4) to exercise were selected. Blood samples were drawn at baseline, the early phase, the late phase, and 24 hours after each stimuli. Eosinofphil cationic protein (ECP) was measured in the serum. Eosinophil granulocytes were separated and the production of leukotriene C4 (LTC4) from purified eosinophfis was measured after stimulation with the calciumionophore. Serum levels of ECP were unchanged at EAR after allergen or exercise challenge. In the dual responder to allergen (group 1), serum ECP level was elevated at LAR and 24 hours after allergen challenge, as compared with the baseline level. On the other hand, in the dual responder to exercise (group 3), it remained unaltered up to 24 hours after exercise challenge. Eosinophils at EAR after allergen or exercise challenge in each group generated the similar amounts of LTC4 as baseline values. In group 1, the production of LTC4 was slightly increased though not significantly at LAR, and significantly increased 24 hours after allergen challenge. In group 3, it was increased significantly at LAR, but restored to the baseline values at 24 hours after exercise challenge. These results indicate that not only allergen but also exercise can activate eosinophils in accordance with LAR. The present findings suggest that LAR to exercise may also have the potential to induce airway eosinophilic inflammation although its duration may be shorter than that of LAR to allergen. Therefore exercise should be understood not only as a triggering factor of bronchoconstriction but also as one that incites or deteriorates airway inflammation.
Asthma*
;
Bronchoconstriction
;
Child
;
Ear
;
Eosinophils*
;
Granulocytes
;
Hand
;
Humans
;
Inflammation
;
Leukotriene C4
8.Association study of polymorphism in leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes with phenotype of asthma and clinical parameters in Korean children.
Jung Yeon SHIM ; Byung Joo KIM ; Young Hwa SONG ; Mi Jin KANG ; So Yeon LEE ; Hyo Bin KIM ; Jinho YU ; Soo Jong HONG
Korean Journal of Pediatrics 2009;52(6):680-688
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.
Asthma
;
Asthma, Exercise-Induced
;
Bronchial Hyperreactivity
;
Bronchial Provocation Tests
;
Child
;
Eosinophils
;
Genotype
;
Humans
;
Leukotriene C4
;
Leukotrienes
;
Lung
;
Phenotype
;
Receptors, Leukotriene
;
Respiratory Function Tests
;
Skin
9.Leukotriene related gene polymorphisms in ASA-intolerant asthma: an association of 5-lipoxygenase haplotype.
Jeong Hee CHOI ; Hae Sim PARK ; Seung Soo SHIN ; Heung Bum OH ; June Hyuk LEE ; Yu Jin SUH ; Choon Sik PARK ; Hyung Doo SHIN
Journal of Asthma, Allergy and Clinical Immunology 2003;23(4):800-809
BACKGROUND AND OBJECTIVES: A recent study has demonstrated a possible involvement of leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, while no significances were noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) for the key enzymes involved in arachidonate metabolism, and cysteinyl leukotriene receptor 1 (CYSLTR1) in a larger scale of Korean population with AIA. MATERIALS AND METHODS: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls (NC) were enrolled. Single base extension method was applied for genotyping of SNPs in 5-lipoxygenase (ALOX5, -1708G>A, 21C>T, 270G>A, 1728G>A), ALOX5 activating protein (FLAP, 218A>G), cyclooxygenase 2 (COX2, -162C>G, 10T>G, 228G>A), LTC4S (-444A>C), and CYSLTR1 (927T>C). Haplotype analyses for ALOX5 were performed as well. RESULTS: There were no significant differences in allele and genotype frequencies of the SNPs among the three groups (p>0.05). However, the frequency of ALOX5-ht1[G-C-G-A] containing genotype in the AIA group was significantly higher than those of the ATA group (p=0.01, OR =5.0, 95%CI=1.54-17.9) and the normal controls (p=0.03, OR=4.5, 95%CI=1.1-18.4) with a dominant model. CONCLUSION: These results suggest a lack of association between FLAP, COX2, LTC4S, and CYSLTR1 gene polymorphisms, and AIA phenotype in Korean population. However, a possible involvement of ALOX5-ht1[G-C-G-A] in AIA development was suggested.
Alleles
;
Arachidonate 5-Lipoxygenase*
;
Aspirin
;
Asthma*
;
Cyclooxygenase 2
;
Genotype
;
Haplotypes*
;
Humans
;
Leukotriene C4
;
Metabolism
;
Phenotype
;
Polymorphism, Genetic
;
Polymorphism, Single Nucleotide
;
Receptors, Leukotriene
10.Mast Cells and Allergic Rhinitis.
Journal of Rhinology 1998;5(2):85-91
That mast cells play a role in acute allergic inflammation by releasing various inflammatory mediators, including histamine, leukotrienes (LT), such as LTC4 and LTD4, and prostaglandins (PG), such as PGD2, is well known. Additionally, mast cells contribute to the development of allergic inflammation also through the release of multifunctional cytokines. The incidence of intraepithelial mast cells (IEMC) is found to be greater in nasal mucosa exposed to an allergen, and the cells are thought to play an important role in producing the immediate allergic reaction. Lamina propira mast cells (LPMC) are known to be the dominant source of TH2 cytokine and are responsible for development of the late phases of an allergic reaction They may upregulate the expression of adhesion molecules on the endothelial cells and induce basophil and eosinophil recruitment. Based on these consideration it can be proposed that mast cell is a initiating cell of allergic reaction in target organ and IEMC and LPMC have capacity to make major contribution to both immediate or late phase reaction of allergic rhinitis.
Basophils
;
Cytokines
;
Endothelial Cells
;
Eosinophils
;
Histamine
;
Hypersensitivity
;
Incidence
;
Inflammation
;
Leukotriene C4
;
Leukotriene D4
;
Leukotrienes
;
Mast Cells*
;
Nasal Mucosa
;
Prostaglandin D2
;
Prostaglandins
;
Rhinitis*