• Allergy, Asthma & Immunology Research
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• 제10권6호
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• pp.628-647
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• 2018

Purpose: Obesity is associated with metabolic dysregulation, but the underlying metabolic signatures involving clinical and inflammatory profiles of obese asthma are largely unexplored. We aimed at identifying the metabolic signatures of obese asthma. Methods: Eligible subjects with obese (n = 11) and lean (n = 22) asthma underwent body composition and clinical assessment, sputum induction, and blood sampling. Sputum supernatant was assessed for interleukin $(IL)-1{\beta}$, -4, -5, -6, -13, and tumor necrosis factor $(TNF)-{\alpha}$, and serum was detected for leptin, adiponectin and C-reactive protein. Untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS)-based metabolic profiles in sputum, serum and peripheral blood monocular cells (PBMCs) were analyzed by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) and pathway topology enrichment analysis. The differential metabolites were further validated by correlation analysis with body composition, and clinical and inflammatory profiles. Results: Body composition, asthma control, and the levels of $IL-1{\beta}$, -4, -13, leptin and adiponectin in obese asthmatics were significantly different from those in lean asthmatics. OPLS-DA analysis revealed 28 differential metabolites that distinguished obese from lean asthmatic subjects. The validation analysis identified 18 potential metabolic signatures (11 in sputum, 4 in serum and 2 in PBMCs) of obese asthmatics. Pathway topology enrichment analysis revealed that cyanoamino acid metabolism, caffeine metabolism, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, pentose phosphate pathway in sputum, and glyoxylate and dicarboxylate metabolism, glycerolipid metabolism and pentose phosphate pathway in serum are suggested to be significant pathways related to obese asthma. Conclusions: GC-TOF-MS-based metabolomics indicates obese asthma is characterized by a metabolic profile different from lean asthma. The potential metabolic signatures indicated novel immune-metabolic mechanisms in obese asthma with providing more phenotypic and therapeutic implications, which needs further replication and validation.

• Proceedings of the Korean Society of Applied Pharmacology
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.254-254
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• 1996

Eosinophils are known to be important effector cells in pathogenesis of asthma. The elucidation of mechanism by which eosinophil survival is regulated in vivo at sites of inflammation is critical tn our understanding of asthma pathogenesis. The maintenance of these cells at site of inflammation depends upon tile balance between its tendency to undergo apoptosis and tile local eosinophil-viability enhancing activity, Qualitative and quantative phenotypic differences have been observed between bronchoalveolar lavage (BAL) and peripheral blood (PB) eosinophils (EOS). We hypothesize that BAL EOS Possess altered functional feature compared to PB EOS. BAL and PB EOS were obtained from ragweed allergic asthmatics after segmental antigen challenge (SAC) at 24 hour or one week, and purified over percoll and CDl6 negative selection. Cells were cultured in duplicate in RPMI, 15% FCS and 1% penicillin/streptomycin without exogenous cytokines. Eosinophil purity and viability was >92%. BAL. EOS viability was 69${\pm}$4.4% versus 39${\pm}$1.6% for PB EOS (p<0.005) at 48 hour time point, and this difference was maintained through day 5 (32${\pm}$7.6% vs. 3.0${\pm}$ 1.4%, p<0.05), Among BAL EOS, those harvested one week after SAC appeared to have an prolonged survival compared to those harvested at 24 hour. Coculture of BAL and PB EOS resulted in significant viability enhancement than expecteed. Direct neutralization of GM-CSF activity, not IL-3 and EL-5, markedly decreased tile survival of BAL EOS in culture, and abrogated tile viability enhancing activity of their culture supernatants in a dose dependent manner. We conclude that BAL EOS activated in vivo possess enhanced viability compared to PB EOS. Mixing and neutralization experiments suggest a role for autocrine production of GM-CSF.

• The Journal of Korean Medicine
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• 제25권2호
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• pp.110-118
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• 2004

Objectives : Based on the changes of quality of life and pulmonary function test, we aimed to identify the effects and side-effects of Gamichuongsangboha-tang and in asthmatic patients. Methods : The subjects consisted of 30 patients with asthma who were treated with Gamichuongsangboha-tang extract for four weeks. Gamichuongsangboha-tang extract is the extracted powder form of the modified herbal decoction Chuongsangboha-whan, which has been used as the traditional therapeutic agent for asthma. Pulmonary function test (PFT) was checked before and after 4 weeks of treatment. Quality of Life QuestionnaireQ for Adult Korean Asthmatics (QLQAKA) was checked before and after 2 and 4 weeks of treatment. Unpleasant symptoms were checked in all patients at 2 weeks and 4 weeks from the beginning of treatment. Results : Treatment with Gamichuongsangboha-tang extract for four weeks resulted in significant increase in $FEV_{1.0}%$, PEFR%, and QLQAKA. The total efficacy rate of QLQAKA in the patient group was 53.3% after 4 weeks. The QLQAKA of the step 2, step 3, and step 4 groups (n=18, 55.6%) classified by global initiative for asthma (GINA) consistently increased, and significant improvement of QLQAKA occurred in the step3 group. In the step 4 group, FEV1.0%, and PEFR% were significantly increased. A total of 15 patients experienced unpleasant symptoms during the first 2 weeks of treatment, but these symptoms disappeared in all but 2 cases with no need of further treatment during the 2nd 2-week period. Conclusions : This study shows that Gamichuongsangboha-tang extract has effects on improvement of pulmonary function and quality of life, especially in persistent symptomatic asthmatics. Obviously further study concerning all these is still necessary.

• Journal of Preventive Medicine and Public Health
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• 제40권1호
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• pp.59-63
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• 2007

Objectives : Nitrogen dioxide $(NO_2)$ has been inconsistently associated with gradual decreases in lung function. Here, we studied the effects of $NO_2$ exposure in asthmatics by examining the association between changes in lung function and concentrations of $NO_2$ which were personally measured. Methods : Peak expiratory flow (PEF) and daily personal exposures to $NO_2$ were recorded on 28 patients with asthma (confirmed by methacholine provocation test) over 4 weeks. We used generalized estimating equations to assess the relationship between personal $NO_2$ exposure and PEF, adjusting for potential confounders such as age, gender, outdoor particulate matter, temperature, humidity, and exposure to environmental tobacco smoke. Results : The personal $NO_2$ exposures were higher than the corresponding ambient levels. The mean personal: ambient ratio for $NO_2$ was 1.48. The personal $NO_2$ exposures were not associated with the morning PEF, evening PEF, or the diurnal PEF variability. However, environmental tobacco smoke was negatively associated with both the morning and evening PEF. Conclusions : Among the asthmatic adults who participated in this study, we found no apparent impact of personal $NO_2$ exposures on the peak expiratory flow.

• Tuberculosis and Respiratory Diseases
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• 제42권4호
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• pp.447-454
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• 1995

Cytokine release from alveolar macrophages and subsequent interaction of these cytokines with the bronchial epithelium can induce epithelial cells to release inflammatory mediators. Nitric oxide(NO), a highly reactive gas formed from arginine by nitric oxide synthase(NOS), is known to be involved in inflammation and edema formation, and the inducible form of NOS(iNOS) can be increased by cytokines. In this context, we hypothesized that lung epithelial cells could be stimulated by cytokines released by alveolar macrophages to express iNOS. To test this hypothesis, the murine lung epithelial cell line, LA-4, or the human lung epithelial cell line, A549, were stimulated with culture supernatant fluids from alveolar macrophages. NO production was assessed by evaluating the culture supernatant fluids for nitrite and nitrate, the stable end products of NO. Both murine and human cell culture supernatant fluids demonstrated an increase in nitrite and nitrate which were time- and dose-dependent and attenuated by $TNF{\alpha}$ and IL-$1{\beta}$ antibodies(p<0.05, all comparisons). Consistent with these observations, cytomix a combination of $TNF{\alpha}$, IL-$1{\beta}$, and $\gamma$-interferon, stimulated the lung epithelial cell lines as well as primary cultures of human bronchial epithelial cells to increase their NO production as evidenced by an increase in nitrite and nitrate in their culture supernatant fluids, an increase in the iNOS staining by immunocytochemistry, and an increase in iNOS mRNA by Northern blottin(p<0.05, all comparisons). The cytokine effects on iNOS were all attenuated by dexamethasone. To determine if these in vitro observations are reflected in vivo, exhaled NO was measured and found to be increased in asthmatics not receiving corticosteroids. These data demonstrate that alveolar macrophage derived cytokines increase iNOS expression in lung epithelial cells and that these in vitro observations are mirrored by increased exhaled NO levels in asthmatics. Increased NO in the lung may contribute to edema formation and airway narrowing.

• Tuberculosis and Respiratory Diseases
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• 제44권4호
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• pp.836-843
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• 1997

Background : The prevalence of Gastro-esophageal reflux(GER) in patients with asthma is estimated to be 50~60% and treatment of GER has been shown to improve asthma symptoms in Western. But GER has been known to be less common in Eastern and GER prevalence rates in asthmatics are not available in Korea. Method : We compared the prevalence rate of GER in 42 patients with asthma to that in 20 healthy normal controls and examed the efficacy of new prokinetic drug, cisapride(40mg/day, 8weeks) in patients with GER and asthma. For acid GER to be considered pathological, 24 hour esophageal pH monitoring should reveal values exceeding upper limit of 95 percentile for at least one of 6 parameter of DeMesseter's table. Result : The results showed GER was more common in patients with asthma(11/42, 26.2%) than normal controls(3/20, 15%) and asthmatics group showed a significant longer supine time pH<4(%) and total time pH<4(%), and more reflux episodes as compared with normal control group. After 4 asthmatics with GER were treated with cisapride, their asthma symtom scores, FEV1 and composite scores of pH monitoring were improved. Conclusion : GER is more common in asthmatics than in normal controls in Korea and prepulsid reduces asthma symptoms in patients with GER and asthma.

• Tuberculosis and Respiratory Diseases
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• 제67권6호
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• pp.506-511
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• 2009

Background: The smoking prevalence in asthma patients are similar to those in the general population. Asthma and active cigarette smoking can interact to create more severe symptoms, an accelerated decline in lung function and impaired therapeutic responses. Accordingly, asthmatics with a history of smoking were examined to define the clinical characteristics and lung function of smoking asthmatics. Methods: The medical records of 142 asthmatics with a known smoking history were reviewed. The patients were divided into three groups according to their smoking history - current smokers, former smokers and non-smokers. The clinical characteristics, lung function, and annual declines of the forced expiratory volume in one second ($FEV_1$) were compared. Results: Fifty-three of the 142 patients (37%) were current smokers, 24 were former smokers (17%) and 65 were non-smokers (45%). The patients with a hospital admission history during the previous year included 16 current smokers (30%), 4 former smokers (17%) and 7 non-smokers (11%) (p=0.02). The mean $FEV_1$ (% predicted) was 76.8${\pm}$19.8%, 71.6${\pm}$21.1% and 87.9${\pm}$18.7% for current smokers, former smokers and non-smokers, respectively (p< 0.001). The $FEV_1$/forced vital capacity (FVC) (ratio, %) values were 63.6${\pm}$12.6%, 59.3${\pm}$14.9% and 72.1${\pm}$11.8% in current smokers, former smokers and non-smokers, respectively (p<0.001). The corresponding mean values for the individual $FEV_1$ slopes were not significant (p=0.33). Conclusion: Asthmatic smokers demonstrated higher hospital admission rates and lower lung function. These findings suggest that the smoking history is an important predictor of a poor clinical outcome in asthma patients.

• Clinical and Experimental Pediatrics
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• 제52권6호
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• pp.680-688
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• 2009

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.

• Tuberculosis and Respiratory Diseases
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• 제42권1호
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• pp.1-10
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• 1995

Background: It has been well known that bronchial asthma is a chronic inflammatory disorder. The "activation" of lymphocytes has a significant role in the pathogenesis of bronchial asthma. Among these lymphocytes, TH2-like rather than TH1-like lymphoytes are activated in the bronchial tissues from patients with atopic bronchial asthma. However, the difference of cytokines expression is not well documented between the atopic normal subjects and atopic asthmatics. Methods: Bronchial tissues were obtained from the tweleve atopic and non-atpoic asthmatics and tweleve atopic and non-atopic healthy subjects for in stiu hybridizatin of IL-2, IL-4, IL-5, and INF-$\gamma$. The probe of cytokines were tagged with digoxigenin by random priming method. Results: The infiltration of many inflammatory cells on submucosa and denuded epithelium were observed in the bronchial tissue from patients with bronchial asthma. The RNase-treated bronchial tissues did not have the brown signal on the tissue, but, RNasc-untreated bronchial tissues had the positive brown signal on the inflammatory cells under the basement membrane. The IL-2 positive signals were detected in 2 cases, IFN-$\gamma$ in 1 casc, IL-4 in 2 cases, IL-5 in 2 cases among 6 non-atopic healthy subjects. The atopic healthy subjects showed 1 case of positive signal of IL-2 and IFN-$\gamma$, but did not show any signals of IL-4 and IL-5. The positive signals of IL-2 were detected in 4 cases among 6 atopic and 6 non-atopic asthmatics, 2 cases and 1 case of IFN-$\gamma$ respectively, 4 cases and 3 cases of IL-4 respectively, 4 cases and 3 cases of IL-5 respectively. Conclusion: The lymphocytes were activated in the bronchus of asthmatics. Among lymphocytes, TH2-like lymphocytes may be involved in the pathogenesis of bronchial asthma. However, futher study with immunohistochemical stain may be necessary for defining the source of cytokines, because of TH2-like lymphocytes were also activated in some atopic healthy subjects.

• Tuberculosis and Respiratory Diseases
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• 제54권2호
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• pp.191-198
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• 2003

Background : The pathological features in asthmatic airway remodeling are diverse. The aim of this study was to examine the degree of airway vascularity in relation to the other remodeling parameters in asthmatics. Methods : Bronchial biopsies were done in 34 asthmatic patients, and 6 control subjects. The basement membrane thickness and the subepithelial thickness were measured in the hematoxylin-eosin stained tissue, and the degree of vascularity was measured using type IV collagen immunostaining. Results : 1) Compared to the control subjects, the asthmatics showed a significant increase in the basement membrane thickness ($6.92{\pm}2.01{\mu}m$ vs $9.67{\pm}2.84{\mu}m$, p<0.05) and the subepithelial thickness ($44.49{\pm}31.92{\mu}m$ vs $121.22{\pm}72.79{\mu}m$, p<0.05). 2) Compared to the control subjects, the asthmatics showed a significant increase in the vascular area per unit submucosal area ($4.51{\pm}2.13%$ vs $10.32{\pm}6.08%$, p<0.05). In addition, the number of vessels per unit submucosal area showed an increased tendency without statistical significance. 3) In the asthmatics, the number of vessels and the vascular area per unit submucosal area showed no correlation with the basement membrane thickness, the subepithelial thickness, the severity, the forced expiratory volume in 1 second($FEV_1$), and the methacholine provocative concentration 20($PC_{20}$). Conclusion : This study showed that vascularity was an important parameter in asthmatic airway remodeling but it was not related to the other remodeling parameters such as the basement membrane thickness and the subepithelial thickness. Each of these asthmatic remodeling parameters may have a different clinical significance. Therefore, further studies will be needed.