WCIM 2014
4 32nd World Congress of Internal Medicine (October 24-28, 2014)
OS-ALG-01 Allergy
Progranulin Level Correlates with Degree of Airway Obstruction in Asthma Patients
So Young PARK1, You Sook CHO1, Bomi SHIN1, Hyo Jung KIM1, So-Young PARK1, Sun- Young YOON1, Gyong Hwa HONG2, Kyoung-Young LEE2, Mi-Young PARK2, Sunjoo PARK2, Hyouk-Soo KWON1, Tae-Bum KIM1, Hee-Bom MOON1
Asan Medical Center, University of Ulsan College of Medicine, Korea1, Asan Institute for Life Sciences, Korea2
Background: Progranulin is a pleiotrophic protein known to function in various phys- iological and disease processes. Progranulin concentration negatively correlated with mediators of neutrophilic inflammation in COPD and it was implicated to have an anti-infl ammatory role. However, it has not been studied in asthma and specifi cally through what mechanistic pathway progranulin exerts its anti-infl ammatory effect.
As a pilot study, we aimed to identify the presence of progranulin in asthma in order to relate with mechanism study in the future, which is another typical chronic airway infl ammatory disease.
Methods: Progranulin levels in serum were measured by ELISA in asthma patients (n=475) and normal subjects (n=43) and was compared with pulmonary function and other various clinical parameters.
Results: Progranulin concentration was significantly lower in asthmatics than in healthy subjects (25.51±6.72 vs 33.92±10.99, p<0.001). Progranulin level was com- pared within asthma patients according to their degree of airway obstruction, and the level showed positive correlation with FEV1% predicted. (R=0.400, p<0.001) Patients diagnosed with asthma/COPD overlap syndrome(n=39) showed lower progranulin level (21.88±5.96 vs 25.84±6.70, p<0.001) and poor lung function (FEV1% predicted, 57.00±17.63 vs 77.20±18.81, p<0.001) compared with patients with asthma(n=436) when subgroup analysis was performed.
Conclusions: The results demonstrate progranulin concentration is lower in asthmatics and the level correlates with the degree of airway obstruction. Progranulin may be associated with pathogenesis of severe asthma with fi xed airway obstruction.
OS-ALG-02 Allergy
The Formation of Endoplasmic Reticulum-Mitochondria Complex Contributes to the Pathogenesis of Severe Bronchial Asthma
Yong Chul LEE1, So Ri KIM1, Dong Im KIM1, Kyung Bae LEE1, Yang Keun RHEE1, Heung Bum LEE1, Seoung Ju PARK1, Yeong Hun CHOE1, Seung Yong PARK1
Chonbuk National University Hospital, Korea1
Background: Under stress conditions, endoplasmic reticulum (ER) loses the homeostasis in its functions, which is defi ned as ER stress. In fact, ER stress has been suggested to be involved in the infl ammatory component of chronic diseases including bronchial asthma.
The NLRP3 infl ammasome is a molecular platform activated upon signs of cellular ‘danger’
to trigger innate immune defenses. Moreover, association between NLRP3 and mito- chondria comes from the observation that activated NLRP3 appears to traffi c from the ER to perinuclear areas similarly to mitochondria-associated ER membranes (MAMs).
Methods: In this study, we investigated whether the allergen-induced cellular stress evokes the conformational association between ER and mitochondria in the airway infl ammatory cells and which are involved in the pathogenesis of bronchial asthma using confocal and electron-microscopic analysis with various molecular biological analytic methods.
Results: The mice sensitized with OVA and LPS and then challenged with OVA (OVALPS- OVA mice) mice showed the typical features of neutrophilic asthma; increased airway inflammatory cells, the pathologic changes, the increased levels of Th2 cytokines in lungs of OVALPS-OVA mice, increased the expression of ER stress markers and NLRP3, and increased bronchial hyperresponsiveness. Interestingly, confocal analysis and elec- tron-microscopic fi ndings revealed that in BAL cells from OVALPS-OVA mice, the ER and mitochondria get closed each other even seemed to be united one compared to the fi nding of cells from control mice. 4-PBA, an ER stress regulator signifi cantly reduced the increases in infl ammatory cytokines, mitochondrial ROS generation, airway infl ammation, and bronchial hyperresponsiveness.
Conclusions: These fi ndings indicate that the development of ER-mitochondria complex induced by ER stress in airway infl ammatory cells may be implicated in the pathogenesis of bronchial asthma, providing the novel therapeutic target for bronchial asthma.
OS-ALG-03 Allergy
Analysis of Severe Asthma Phenotypes by Using Quan- titative Computed Tomography: A Cross-Sectional Study
Ju-Young KIM1, Sujeoung KIM2, Kwang Nam JIN3, Chang Hyun LEE3, Woo-Jung SONG4, Hye-Ryun KANG4, Heung-Woo PARK4, Kyung-Up MIN4, Sang-Heon CHO4 Seoul National University Bundang Hospital, Korea1, Kyungpook National University School of Medicine, Korea2, Seoul National University College of Medicine, Korea3, Seoul National University College of Medicine, Korea4
Background: Severe asthma is a heterogeneous disease with various phenotypic charac- teristics. Assessment of different airway remodeling patterns by computed tomography (CT) is a new approach that may be useful in the classifi cation of asthma phenotypes.
Methods: We prospectively recruited patients with severe asthma at the Seoul Na- tional University Hospital, and performed CT scans along with pulmonary function test, induced sputum test, fractional exhaled nitric oxide, and serum cytokine measure- ments. Two radiologists blinded to clinical information performed qualitative analysis of each CT and determined the phenotype by consensus. Quantitative CT measures of bronchial wall thickening, emphysema, and air trapping were also investigated.
Association between the radiologic fi ndings and clinical parameters were assessed by univariate and multivariate regression analysis.
Results: A total of 39 subjects were classifi ed into one of four CT phenotypes: large or medium sized airway remodeling, type 1 (n=17); small airway remodeling, type 2 (n=6);
near-normal, type 3 (n=14); and abundant subcutaneous and visceral fat tissue, type 4 (n=2). The type 1 group demonstrated higher sputum eosinophil percentage and lower FEV1/FVC, and type 2 showed male-predominance, higher percentage of smokers, and lower FEV1/FVC compared with the near-normal group. Quantitative airway analysis revealed signifi cantly increased bronchial wall thickness and luminal diameter in the type 1 phenotype and higher median scores for emphysema and air trapping in the type 2 phenotype. Sputum eosinophil (%) moderately correlated with bronchial wall thickness after adjustment for lung function and smoking (p=0.016, r=0.598). Serum IFN-γ, IL-8, and IL-10 were signifi cantly increased in the type 1 phenotype.
Conclusions: Severe asthma is a heterogeneous disease, but is indiscernible from its clinical features. Through CT imaging, we successfully classifi ed severe asthma into 4 different types with distinct characteristics.
OS-ALG-04 Allergy
Association of Autophagy Related Gene Polymorphisms with Neutrophilic Asthma Phenotype in Korean Adult Asthmatics
Le Duy PHAM1, Seung-Hyun KIM1, Purevsuren LOSOL2, Eun-Mi YANG1, Yoo-Seob SHIN1, Young-Min YE1, Hae-Sim PARK1
Ajou University School of Medicine, Korea1, Health Sciences University of Mogolia, Mongolia2 Background: Role of autophagy in neutrophil function and the association of auto- phagy and autophagy related gene (ATG) polymorphisms with asthma susceptibility were suggested. In this study, we investigated the association of ATG5 and ATG7 pol- ymorphisms with asthma risk, severity and neutrophilic phenotype of asthma.
Methods: We recruited 408 asthma patients and 201 healthy controls (NC). Sputum neutrophil counts were determined by H&E staining. Serum IL-8 levels were measured by ELISA. ATG5 gene polymorphisms (-769T>C, -335G>A and 8830C>T) and ATG7 gene polymorphisms (-100A>G and 25108G>C) were genotyped. The functional activ- ities of ATG5 -769T>C and -335G>A variants were investigated by luciferase reporter assays.
Results: No associations of ATG5 and ATG7 gene polymorphisms with asthma sus- ceptibility and severity were found. ATG5 -769T>C and -335G>A were in complete linkage disequilibrium. In the asthma group, GA/AA genotypes at ATG5 -335G>A were associated with higher neutrophil counts in sputum (P<0.05); CC/TT genotype at ATG5 8830C>T associated with lower % FEV1 predicted value (P<0.05). DNA fragments containing ATG5 -769T and -335G alleles had higher promoter activities compared to those with -769C and -335A in both human airway epithelial cells (A549, P<0.01) and human mast cell (HMC-1, P<0.001). GG and CC genotype at ATG7 -100A>G and 25108G>C were signifi cantly associated with high serum levels of IL-8 (P<0.05 for both variants).
Conclusions: Polymorphisms of ATG5 and ATG7 genes could contribute to neutrophilic phenotype in the pathogenesis of adult asthma.
