June-Hyuk Lee

ADAM33 polymorphism : association with bronchial hyper-responsiveness in Korean asthmatics

Background A disintegrin and metalloprotease 33 (ADAM33) is expressed in the lung by fibroblasts and bronchial smooth muscle cells. Given its structure and cellular provenance, ADAM33 may be associated with airway remodelling and bronchial hyper‐responsiveness. Single nucleotide polymorphisms (SNPs) and haplotypes of the ADAM33 gene have previously been associated with asthma susceptibility in the Caucasian population.

Interleukin 3 (IL3) polymorphisms associated with decreased risk of asthma and atopy.

AbstractCytokines, having central functions in immunological and inflammatory process, are always expected to play important roles in the pathogenesis of various diseases, such as asthma. Genetic polymorphisms of those cytokine and cytokine receptor genes are the focus of genetic association studies. In an effort to identify gene(s) whose variant(s) are involved in the development of asthma, we examined the genetic effects of 19 single nucleotide polymorphisms in eight cytokine and cytokine receptor genes, including IL1A, IL1B, IL2, IL3, IL4, IL8, IL10, and IL5RA, on asthma and atopy. Nineteen single nucleotide polymorphisms in eight cytokine and cytokine receptor genes were genotyped using the single-base extension method in a Korean asthma cohort (n=723). Logistic regression and multiple regressions were used for statistical analyses controlling for smoking, age, and gender as covariables. Genetic association analysis of polymorphisms revealed that one exonic (exon 1), IL3+79T>C (Ser27Pro), showed significant association with the risk of asthma and atopy. The Pro allele had shown dominant and protective effects on development of asthma in nonatopic subjects (P=0.002) and also showed significant association with the risk of atopy in normal control subjects (P=0.007). This information about the genetic association of important genes with asthma might provide valuable insights into strategies for the pathogenesis of asthma and atopy.

Association of interleukin 18 (IL18) polymorphisms with specific IgE levels to mite allergens among asthmatic patients

Background:  Allergy is regarded as a multifactorial condition. Its onset and severity are influenced by both genetic and environmental factors. Identification of genetic factors involved in asthma development and related phenotypes is a major task in understanding the genetic background of asthma. The possible involvement of IL18 polymorphisms in asthma was examined in a Korean asthma cohort.

Differences in radiological/HRCT findings in eosinophilic bronchitis and asthma: implication for bronchial responsiveness

Background: Airway hyperresponsiveness in asthmatics is considered to be one of the major consequences of airway inflammation and remodelling. Airway responsiveness is normal in patients with eosinophilic bronchitis (EB), despite eosinophilic inflammation of the airways comparable to that which occurs in asthmatics. Comparisons between asthma and EB should clarify the changes in airway morphology that are related specifically to AHR in asthmatics. Methods: Eighteen asthmatic patients, 15 patients with EB, and 11 healthy subjects were recruited. Airway wall area percentage (WA%), centrilobular prominence, and air trapping were compared using thin slice section computed tomography. Results: WA% was significantly greater in asthmatics than in patients with EB (72 (3.1)% v 54 (2.1)%, p = 0.032) and was similar in EB patients and controls (54 (2.1)% v 57 (1.8)%, p>0.05). Centrilobular prominence and air trapping were similar in EB patients and asthmatics and were significantly greater than in controls. Conclusion: WA% rather than air trapping or centrilobular prominence may be associated with the airway hyperresponsiveness that occurs in asthmatics but not in patients with EB.

Additive Effect of Diesel Exhaust Particulates and Ozone on Airway Hyperresponsiveness and Inflammation in a Mouse Model of Asthma

Allergic airway diseases are related to exposure to atmospheric pollutants, which have been suggested to be one factor in the increasing prevalence of asthma. Little is known about the effect of ozone and diesel exhaust particulates (DEP) on the development or aggravation of asthma. We have used a mouse asthma model to determine the effect of ozone and DEP on airway hyperresponsiveness and inflammation. Methacholine enhanced pause (Penh) was measured. Levels of IL-4 and IFN-γ were quantified in bronchoalveolar lavage fluids by enzyme immunoassays. The OVA-sensitized-challenged and ozone and DEP exposure group had higher Penh than the OVA-sensitized-challenged group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone exposure group. Levels of IFN-γ were decreased in the OVA-sensitized-challenged and DEP exposure group and the OVA-sensitized-challenged and ozone and DEP exposure group compared to the OVA-sensitized-challenged and ozone exposure group. Levels of IL-4 were increased in the OVA-sensitized-challenged and ozone exposure group and the OVA-sensitized-challenged and DEP exposure group, and the OVA-sensitized-challenged and ozone and DEP exposure group compared to OVA-sensitized-challenged group. Co-exposure of ozone and DEP has additive effect on airway hyperresponsiveness by modulation of IL-4 and IFN-γ suggesting that DEP amplify Th2 immune response.

Risk factors related to fixed airway obstruction in patients with asthma after antiasthma treatment

BACKGROUND There are many unanswered questions about the role of airway remodeling in asthma. OBJECTIVE To evaluate the physiologic factors related to airway remodeling after antiasthma drug treatment for 1 year. METHODS We gave 582 patients with asthma long-term control medication for 1 year according to the severity of their asthma. Airway remodeling was defined using forced expiratory volume in 1 second/forced vital capacity and a predicted forced expiratory volume in 1 second of less than 75% after antiasthma treatment. RESULTS Of the 582 patients, 49 (8.4%) had airway remodeling. Severe asthma resulted in more airway remodeling than mild-to-moderate asthma. Asthmatic patients with airway remodeling were significantly older and had a longer duration of asthma. Asthmatic patients with airway remodeling had more emphysema on high-resolution computed tomography, a higher rate of near-fatal asthma attacks, a lower percentage of sputum eosinophils, a lower atopy frequency, a greater response to short-acting bronchodilators, and a lower body mass index (BMI) than those without airway remodeling. Age, asthma duration, and BMI were important discriminators of airway remodeling. CONCLUSION Nonatopy, asthma duration, emphysema on high-resolution computed tomography, sputum eosinophils, age, and BMI before antiasthma treatment are important factors related to airway remodeling in patients with asthma.

Genetic interactions model among Eotaxin gene polymorphisms in asthma

AbstractEotaxin family (Eotaxin 1,2 and 3) recruits and activates CCR3-bearing cells such as eosinophil, mast cells, and Th2 lymphocytes that play a major role in allergic disorders. We examined the polygenetic effects of the Eotaxin gene family in a Korean population. Gene-gene interactions were tested using a multistep approach with multifactor dimensionality reduction (MDR) method between asthmatics and normal controls. The overall best MDR model of the main effect single nucleotide polymorphisms (SNPs) included EOT2 + 1272A > G and EOT3 + 77C > T (model 1) [testing accuracy 0.597, cross-validation consistency (CVC) 10/10, P < 0.001]. The overall best MDR model of the SNPs with no main effects included EOT2 + 304C > A, EOT3 + 716A > G, and EOT3 + 1579G > A (model 2) (testing accuracy 0.616, CVC 10/10, P < 0.001). Model 3 was obtained by including the MDR variables for models 1 and 2. This new composite model predicted asthma with better accuracy than either model 1 or model 2 (testing accuracy 0.643, CVC 10/10, P < 0.001). The detection of statistical interaction models is one evidence of gene-gene interactions among Eotaxin genes, and this interaction is thought to influence the development of asthma. Although the models are limited to determining statistical interactions within a population, they may be useful for identifying groups at high risk of developing asthma.

Antioxidant responsiveness in BALB/c mice exposed to ozone.

Background: A single, acute exposure to ozone has been shown to modify the antioxidant defense mechanism in the respiratory tract. Objective: The aim of this study was to evaluate the effects of ozone exposure on antioxidant response in BALB/c mice. Methods: We measured enhanced pause of breathing (Penh) as a marker of airway obstruction using barometric whole-body plethysmography before and after ozone exposure [groups (n = 6): filtered air, 0.12 ppm, 0.5 ppm, 1 ppm, 2 ppm] for 3 h. Antioxidant levels were measured using high-performance liquid chromatography with electrochemical detection in bronchoalveolar lavage (BAL) fluid and lung tissue homogenates. Results: Malondialdehyde concentrations in lung tissue homogenates were significantly increased in the group exposed to 2-ppm ozone compared to the filtered air group. Uric acid and γ-tocopherol concentrations in BAL fluid were significantly increased in the ozone exposure group compared to the filtered air group (p < 0.01). Uric acid concentrations were increased in a concentration-dependent manner according to ozone concentration to which the animals were exposed. Increases in Penh after ozone exposure were significantly higher in an ozone concentration-dependent manner. The proportion of neutrophils in BAL fluid was significantly higher in the group exposed to 2 ppm than in the filtered air and the group exposed to 0.12 ppm (p < 0.01, respectively). The level of ascorbate correlated with the level of γ-tocopherol. Conclusion: These findings suggest that antioxidant responses may serve as a protective mechanism against a range of oxidants in BALB/c mice exposed to ozone.

Autologous Serum Skin Test for Autoantibodies Is Associated with Airway Hyperresponsiveness in Patients with Asthma

Background: Autoimmune diseases have been implicated as a cause of intrinsic asthma; however, there is little data on the role of autoimmunity in the pathogenesis of asthma. Objective: The purpose of this study was to investigate circulating functional autoantibodies against the high-affinity IgE receptor FcΕRI or IgE in patients with asthma. Methods: Twenty-eight patients with asthma and 19 control subjects were included. All subjects were skin tested with autologous serum to assess for the potential presence of receptor FcΕRI or IgE autoantibodies. If the serum-induced wheal diameter was 1.5 mm larger than the histamine-induced wheal diameter and that was 3 mm larger than the saline-induced wheal diameter at 30 min, the reaction was defined positive. Results: Of the 47 total subjects (both asthma patients and control subjects), 13 (27.7%) had a positive autologous serum skin test (ASST). Of the 28 asthma patients, 8 (28.6%) were regarded as having autoimmune origin. Autoantibodies against FcΕRI or IgE were found in asthma patients, irrespective of atopic status (atopy+ 3/13 vs. atopy– 5/15). The wheal diameter related to ASST was not related to atopy. Asthma patients with ASST-positive results as compared with patients with ASST-negative results exhibited a significant increased airway hyperresponsiveness (PC20 methacholine, 2.70 ± 1.27 vs. 9.08 ± 2.35; p < 0.026). Conclusion: Our data demonstrate that aberrant autoantibodies against the high-affinity IgE receptor FcΕRI or IgE are related to airway hyperresponsiveness in patients with asthma.

The Impact of Smoking on Clinical and Therapeutic Effects in Asthmatics

Smoking is associated with poor symptom control and impaired therapeutic responses in asthma. A total of 843 patients with asthma were recruited. The patients received treatment for 1 yr according to the severity of their asthma. We compared the forced expiratory volume in 1 sec (FEV1), the ratio of FEV1 to forced vital capaity (FVC), atopy, total IgE, emphysema on high-resolution computed tomography (HRCT), the number of near-fatal asthma attacks, and physiological fixed airway obstruction between the smoking and nonsmoking groups. The study population consisted of 159 (18.8%) current smokers, 157 (18.7%) ex-smokers, and 525 (62.5%) nonsmokers. Although the prevalence of atopy was not different between the smoking and nonsmoking groups, the total IgE was higher among the smokers than the nonsmokers. Compared with the nonsmoking group, the smokers had a lower FEV1 % predicted and forced expiratory flow between 25 and 75% of FVC. A greater prevalence of emphysema and a significantly higher number of asthmatic patients with fixed airway obstruction were detected in the smoking versus nonsmoking group. The 37.5% of asthmatic patients who were former or current smokers showed decreased pulmonary function and increased IgE, emphysema on HRCT, and fixed airway obstruction, indicating that smoking can modulate the clinical and therapeutic responses in asthma.