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1.  Role of AMP-Activated Protein Kinase (AMPK) in Smoking-Induced Lung Inflammation and Emphysema 
AMP-activated protein kinase (AMPK) not only functions as an intracellular energy sensor and regulator, but is also a general sensor of oxidative stress. Furthermore, there is recent evidence that it participates in limiting acute inflammatory reactions, apoptosis and cellular senescence. Thus, it may oppose the development of chronic obstructive pulmonary disease.
To investigate the role of AMPK in cigarette smoke-induced lung inflammation and emphysema we first compared cigarette smoking and polyinosinic-polycytidylic acid [poly(I:C)]-induced lung inflammation and emphysema in AMPKα1-deficient (AMPKα1-HT) mice and wild-type mice of the same genetic background. We then investigated the role of AMPK in the induction of interleukin-8 (IL-8) by cigarette smoke extract (CSE) in A549 cells.
Cigarette smoking and poly(I:C)-induced lung inflammation and emphysema were elevated in AMPKα1-HT compared to wild-type mice. CSE increased AMPK activation in a CSE concentration- and time-dependent manner. 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an AMPK activator, decreased CSE-induced IL-8 production while Compound C, an AMPK inhibitor, increased it, as did pretreatment with an AMPKα1-specific small interfering RNA.
AMPKα1-deficient mice have increased susceptibility to lung inflammation and emphysema when exposed to cigarette smoke, and AMPK appears to reduce lung inflammation and emphysema by lowering IL-8 production.
PMCID: PMC4311035  PMID: 25653691
AMP-Activated Protein Kinases; Pulmonary Disease, Chronic Obstructive; Emphysema; Inflammation; Interleukin-8
2.  Clinical Characteristics and Survival of Korean Idiopathic Pulmonary Arterial Hypertension Patients Based on Vasoreactivity 
Journal of Korean Medical Science  2014;29(12):1665-1671.
We aimed to identify a vasoreactive subset of patients with idiopathic pulmonary arterial hypertension (IPAH) in Korea and to show their clinical characteristics and prognosis. Data on patients who were diagnosed with IPAH at Asan Medical Center between January 1994 and March 2013 were retrospectively collected. Acute vasodilator testing was performed with inhaled nitric oxide during diagnostic right heart catheterization. A positive acute response was defined as a reduction in mean pulmonary arterial pressure (PAP) ≥10 mmHg to an absolute level of mean PAP <40 mmHg without a decrease in cardiac output. Among a total of 60 IPAH patients included for analysis, 9 (15%) showed a positive acute response to acute vasodilator testing. Acute responders showed significantly lower peak velocity of a tricuspid regurgitation jet on echocardiography (4.1±0.3 m/s vs. 4.6±0.6 m/s; P=0.01) and significantly lower mean PAP hemodynamically (47±10 mmHg vs. 63±17 mmHg; P=0.003) than non-responders at baseline. The survival rate of acute responders was 88% at 1, 3, 5, and 10 yr, respectively, which was significantly higher than that of non-responders (85%, 71%, 55%, and 40%, respectively; P=0.029). In conclusion, Korean IPAH patients with vasoreactivity showed better baseline hemodynamic features and survival than those without vasoreactivity.
Graphical Abstract
PMCID: PMC4248588  PMID: 25469067
Hypertension, Pulmonary; Vasodilator Agents; Calcium Channel Blockers; Survival Rate
3.  Relationship of Vitamin D Binding Protein Polymorphisms and Lung Function in Korean Chronic Obstructive Pulmonary Disease 
Yonsei Medical Journal  2014;55(5):1318-1325.
Multiple genetic factors are associated with chronic obstructive pulmonary disease (COPD). The association of gene encoding vitamin D binding protein (VDBP, GC) with COPD has been controversial. We sought to investigate the types of GC variants in the Korean population and determine the association of GC variants with COPD and lung function in the Korean population.
Materials and Methods
The study cohort consisted of 203 COPD patients and 157 control subjects. GC variants were genotyped by the restriction fragment-length polymorphism method. Repeated measures of lung function data were analyzed using a linear mixed model including sex, age, height, and pack-years of smoking to investigate the association of GC genetic factors and lung function.
GC1F variant was most frequently observed in COPD (46.1%) and controls (42.0%). GC1S variant (29.0% vs. 21.4%; p=0.020) and genotype 1S-1S (8.3% vs. 3.4%; p=0.047) were more commonly detected in control than COPD. According to linear mixed model analysis including controls and COPD, subjects with genotype 1S-1S had 0.427 L higher forced expiratory volume in 1 second (FEV1) than those with other genotypes (p=0.029). However, interaction between the genotype and smoking pack-year was found to be particularly significant among subjects with genotype 1S-1S; FEV1 decreased by 0.014 L per smoking pack-year (p=0.001).
This study suggested that GC polymorphism might be associated with lung function and risk of COPD in Korean population. GC1S variant and genotype 1S-1S were more frequently observed in control than in COPD. Moreover, GC1S variant was more common in non-decliners than in rapid decliners among COPD.
PMCID: PMC4108818  PMID: 25048491
Vitamin D binding protein; polymorphism; lung function; chronic obstructive pulmonary disease
4.  Study Design and Outcomes of Korean Obstructive Lung Disease (KOLD) Cohort Study 
The Korean Obstructive Lung Disease (KOLD) Cohort Study is a prospective longitudinal study of patients with chronic obstructive pulmonary disease (COPD), asthma, or other unclassified obstructive lung diseases. It was designed to develop new classification models and biomarkers that predict clinically relevant outcomes for patients with obstructive lung diseases.
Patients over 18 years old who have chronic respiratory symptoms and airflow limitations or bronchial hyper-responsiveness were enrolled at 17 centers in South Korea. After a baseline visit, the subjects were followed up every 3 months for various assessments.
From June 2005 to October 2013, a total of 477 subjects (433 [91%] males; 381 [80%] diagnosed with COPD) were enrolled. Analyses of the KOLD Cohort Study identified distinct phenotypes in patients with COPD, and predictors of therapeutic responses and exacerbations as well as the factors related to pulmonary hypertension in COPD. In addition, several genotypes were associated with radiological phenotypes and therapeutic responses among Korean COPD patients.
The KOLD Cohort Study is one of the leading long-term prospective longitudinal studies investigating heterogeneity of the COPD and is expected to provide new insights for pathogenesis and the long-term progression of COPD.
PMCID: PMC4021264  PMID: 24851130
Biological Markers; Pulmonary Disease, Chronic Obstructive; Cohort Studies; Longitudinal Studies; Phenotype
5.  Characteristics of stable chronic obstructive pulmonary disease patients in the pulmonology clinics of seven Asian cities 
Background and objectives
Chronic obstructive pulmonary disease (COPD) is responsible for significant morbidity and mortality worldwide. We evaluated the characteristics of stable COPD patients in the pulmonology clinics of seven Asian cities and also evaluated whether the exposure to biomass fuels and dusty jobs were related to respiratory symptoms, airflow limitation, and quality of life in the COPD patients.
This cross-sectional observational study recruited 922 COPD patients from seven cities of Asia. The patients underwent spirometry and were administered questionnaires about their exposure to cigarette smoking, biomass fuels, and dusty jobs in addition to respiratory symptoms and health related quality of life.
Of the patients, there appeared to be variations from city to city in the history of exposure to biomass fuels and dusty jobs and also in respiratory symptoms of cough, phlegm, wheeze, and dyspnea. These symptoms were more frequent in those COPD patients with a history of exposure to biomass fuels than without and those with a history of exposure to dusty jobs than without (P < 0.01 for all comparisons). Airflow limitation was more severe in those COPD patients with a history of exposure to biomass fuels than without (52.2% predicted versus 55.9% of post-bronchodilator forced expiratory volume in 1 second [FEV1], P = 0.009); quality of life was poorer in those with exposure to biomass fuels than without (40.4 versus 36.2 of the St George’s Respiratory Questionnaire [SGRQ] total score, P = 0.001). Airflow limitation was more severe in those COPD patients with a history of exposure to dusty jobs than without (51.2% predicted versus 57.3% of post-bronchodilator FEV1, P < 0.001); quality of life was poorer in those with dusty jobs than without (41.0 versus 34.6 of SGRQ score, P = 0.006).
In Asian cities, the characteristics of COPD patients vary and the history of exposure to biomass fuels or dusty jobs was related to frequency of symptoms, severe airflow limitation, and poor quality of life.
PMCID: PMC3553655  PMID: 23378753
COPD; Asia; biomass; dust
7.  Predictors of Pulmonary Function Response to Treatment with Salmeterol/fluticasone in Patients with Chronic Obstructive Pulmonary Disease 
Journal of Korean Medical Science  2011;26(3):379-385.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and responses to therapies are highly variable. The aim of this study was to identify the predictors of pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD. A total of 127 patients with stable COPD from the Korean Obstructive Lung Disease (KOLD) Cohort, which were prospectively recruited from June 2005 to September 2009, were analyzed retrospectively. The prediction models for the FEV1, FVC and IC/TLC changes after 3 months of treatment with salmeterol/fluticasone were constructed by using multiple, stepwise, linear regression analysis. The prediction model for the FEV1 change after 3 months of treatment included wheezing history, pre-bronchodilator FEV1, post-bronchodilator FEV1 change and emphysema extent on CT (R = 0.578). The prediction models for the FVC change after 3 months of treatment included pre-bronchodilator FVC, post-bronchodilator FVC change (R = 0.533), and those of IC/ TLC change after 3 months of treatment did pre-bronchodilator IC/TLC and post-bronchodilator FEV1 change (R = 0.401). Wheezing history, pre-bronchodilator pulmonary function, bronchodilator responsiveness, and emphysema extent may be used for predicting the pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD.
PMCID: PMC3051085  PMID: 21394306
Pulmonary Disease, Chronic Obstructive; Emphysema; Corticosteroids; Adrenergic beta-Agonists; Respiratory Function Tests
8.  Hyperosmotic Stimulus Down-regulates 1α, 25-dihydroxyvitamin D3-induced Osteoclastogenesis by Suppressing the RANKL Expression in a Co-culture System 
The hyperosmotic stimulus is regarded as a mechanical factor for bone remodeling. However, whether the hyperosmotic stimulus affects 1α, 25-dihydroxyvitamin D3 (1α,25(OH)2D3)-induced osteoclastogenesis is not clear. In the present study, the effect of the hyperosmotic stimulus on 1α,25(OH)2D3-induced osteoclastogenesis was investigated in an osteoblast-preosteoclast co-culture system. Serial doses of sucrose were applied as a mechanical force. These hyperosmotic stimuli significantly evoked a reduced number of 1α,25(OH)2D3-induced tartrate-resistant acid phosphatase-positive multinucleated cells and 1α,25(OH)2D3-induced bone-resorbing pit area in a co-culture system. In osteoblastic cells, receptor activator of nuclear factor κB ligand (RANKL) and Runx2 expressions were down-regulated in response to 1α,25(OH)2D3. Knockdown of Runx2 inhibited 1α,25(OH)2D3-induced RANKL expression in osteoblastic cells. Finally, the hyperosmotic stimulus induced the overexpression of TonEBP in osteoblastic cells. These results suggest that hyperosmolarity leads to the down-regulation of 1α,25(OH)2D3-induced osteoclastogenesis, suppressing Runx2 and RANKL expression due to the TonEBP overexpression in osteoblastic cells.
PMCID: PMC2902809  PMID: 20631890
Hyperosmotic stimulus; TonEBP; Osteoblast; RANKL; Runx2
9.  Three-month Treatment Response and Exacerbation in Chronic Obstructive Pulmonary Disease 
The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients.
Graphical Abstract
PMCID: PMC4278027  PMID: 25552883
Pulmonary Disease, Chronic Obstructive; Forced Expiratory Volume; Disease Progression
10.  Cytoplasmic Localization and Redox Cysteine Residue of APE1/Ref-1 Are Associated with Its Anti-Inflammatory Activity in Cultured Endothelial Cells 
Molecules and Cells  2013;36(5):439-445.
Apurinic/apyrimidinic endonuclease1/redox factor-1 (APE1/ Ref-1) is a multifunctional protein involved in base excision DNA repair and transcriptional regulation of gene expression. APE1/Ref-1 is mainly localized in the nucleus, but cytoplasmic localization has also been reported. However, the functional role of cytoplasmic APE1/Ref-1 and its redox cysteine residue are still unknown. We investigated the role of cytoplasmic APE1/Ref-1 on tumor necrosis factor-α (TNF-α)-induced vascular cell adhesion molecule-1 (VCAM-1) expressions in endothelial cells. Endogenous APE1/Ref-1 was mainly observed in the nucleus, however, cytoplasmic APE1/Ref-1 was increased by TNF-α. Cytoplasmic APE1/ Ref-1 expression was not blunted by cycloheximide, a protein synthesis inhibitor, suggesting cytoplasmic translocation of APE1/Ref-1. Transfection of an N-terminus deletion mutant APE1/Ref-1(29-318) inhibited TNF-α-induced VCAM-1 expression, indicating an anti-inflammatory role for APE1/Ref-1 in the cytoplasm. In contrast, redox mutant of APE1/Ref-1 (C65A/C93A) transfection led to increased TNF-α-induced VCAM-1 expression. Our findings suggest cytoplasmic APE1/Ref-1 localization and redox cysteine residues of APE1/Ref-1 are associated with its anti-inflammatory activity in endothelial cells.
PMCID: PMC3887937  PMID: 24213673
APE1/Ref-1; endothelial cells; TNF-α; VCAM-1
11.  Efficacy of Bronchoscopic Lung Volume Reduction by Endobronchial Valves in Patients with Heterogeneous Emphysema: Report on the First Asian Cases 
Journal of Korean Medical Science  2014;29(10):1404-1410.
Although many patients with severe emphysema have benefited from bronchoscopic lung volume reduction (BLVR) worldwide, experience of BLVR in Asian emphysema patients is scarce. Between July 2012 and March 2013, seven patients with advanced heterogeneous emphysema underwent BLVR in the Asan Medical Center. They had severe dyspnea and poor lung function (Modified Medical Research Council dyspnea scale 3-4; median forced expiratory volume in 1 sec [FEV1], 0.59 L [19.0 % predicted]; median 6-min walk distance [6MWD], 195 m). Endobronchial valves were inserted into the target lobe which was most hyperinflated and least perfused, and had no collateral ventilation with other lobes. Six patients showed clinical improvement after 1 month. Of them, 2 patients improved to dyspnea scale 1 and 4 patients did to scale 2 (P = 0.026). The median FEV1 increased from 0.59 to 0.89 L (51%; P = 0.028) and the median 6MWD increased from 195 to 252 m (29.2%; P = 0.028). Two patients developed a pneumothorax (one requiring drainage) and one patient experienced slight hemoptysis; however, there were no other serious adverse events. BLVR is effective in Asian advanced emphysema patients, with noted clinical improvements in lung function and exercise capacity.
Graphical Abstract
PMCID: PMC4214942  PMID: 25368495
Emphysema; Individualized Medicine; Lung Volume Reduction; Patient Selection; Pulmonary Disease, Chronic Obstructive
12.  Arginase II Inhibited Lipopolysaccharide-Induced Cell Death by Regulation of iNOS and Bcl-2 Family Proteins in Macrophages 
Molecules and Cells  2013;35(5):396-401.
Arginase II catalyzes the conversion of arginine to urea and ornithine in many extrahepatic tissues. We investigated the protective role of arginase II on lipopolysaccharide-mediated apoptosis in the macrophage cells. Adenoviral gene transfer of full length of arginase II was performed in the murine macrophage cell line RAW264.7. The role of arginase II was investigated with cell viability, cytoplasmic histone-associated DNA fragmentation assay, arginase activity, nitric oxide production, and Western blot analysis. Arginase II is localized in mitochondria of macrophage cells, and the expression of arginase II was increased by lipopolysaccharide (LPS). LPS significantly increased cell death which was inhibited by AMT, a specific inducible nitric oxide synthase (iNOS) inhibitor. In contrast, LPS-induced cell death and nitric oxide production were increased by 2-boronoethyl-L-cysteine, a specific inhibitor of arginase. Adenoviral overexpression of arginase II significantly inhibited LPS-induced cell death and cytoplasmic histone-associated DNA fragmentation. LPS-induced iNOS expression and poly ADP-ribose polymerase cleavage were significantly suppressed by arginase II overexpression. Furthermore, arginase II overexpression resulted in a decrease in the Bax protein level and the reverse induction of Bcl-2 protein. Our data demonstrated that inhibition of NO production by arginase II may be due to arginine depletion as well as iNOS suppression though its reaction products. Moreover, arginase II plays a protective role of LPS-induced apoptosis in RAW264.7 cells.
PMCID: PMC3887864  PMID: 23639968
Arginase II; Bax; lipopolysaccharide; macrophage; nitric oxide
13.  Influence of Environmental Exposures on Patients with Chronic Obstructive Pulmonary Disease in Korea 
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation and results from environmental factors and genetic factors. Although cigarette smoking is a major risk factor, other environmental exposures can influence COPD. The purpose of this study is to investigate the clinical characteristics of COPD according to the history of environmental exposure.
The study population comprised of 347 subjects with COPD who were recruited from the pulmonary clinics of 14 hospitals within the Korean Obstructive Lung Disease Study Group. We classified environmental exposures according to history of living near factory, and direct exposure history to firewood or briquette. According to living environmental exposures, we compared the frequency of respiratory symptoms, pulmonary function, quality of life, exercise capacity, and computed tomography phenotypes.
Thirty-one subjects (8.9%) had history of living near factory, 271 (78.3%) had exposure history to briquette, and 184 (53.3%) had exposure history to firewood. Patients with history of living near a factory had a significantly longer duration of sputum, while patients with exposure to firewood tended to have lower forced expiratory volume in one second, and patients with exposure to briquette tended to have lower six minute walk distance.
COPD subjects with the history of living near factory had more frequent respiratory symptoms such as sputum. Our data suggest that environmental exposure may influence clinical phenotype of COPD.
PMCID: PMC4050070
Pulmonary Disease, Chronic Obstructive; Environmental Exposure; Air Pollutants; Occupational Exposure; Fossil Fuels
14.  Causes and Predictive Factors Associated with "Diagnosis Changed" Outcomes in Patients Notified as Tuberculosis Cases in a Private Tertiary Hospital 
The aim of our study was to evaluate the "diagnosis changed" rate in patients notified as tuberculosis (TB) on the Korean TB surveillance system (KTBS).
A total of 1,273 patients notified as TB cases on the KTBS in one private tertiary hospital in 2011 were enrolled in the present study. Patients were classified into three groups: "diagnosis maintained", "diagnosis changed" (initially notified as TB, but ultimately diagnosed as non-TB), and "administrative error" (notified as TB due to administrative errors).
Excluding 17 patients in the "administrative error" group, the "diagnosis maintained" and "diagnosis changed" groups included 1,097 (87.3%) and 159 patients (12.7%), respectively. Common causes of "diagnosis changed" were nontuberculous mycobacterial (NTM) disease (51.7%, 61/118), and pneumonia (17.8%) in cases notified as pulmonary TB, and meningitis (19.5%, 8/41) and Crohn's disease (12.2%) in cases notified as extrapulmonary TB. Being older than 35 years of age (odds ratio [OR], 2.18) and a positive acid-fast bacilli stain (OR, 1.58) were positive predictors and a TB-related radiological finding (OR, 0.42) was a negative predictor for a "diagnosis changed" result via multivariate logistic regression analysis in pulmonary TB cases.
Because of a high "diagnosis changed" rate in TB notifications to the KTBS, the TB incidence rate measured by the KTBS may be overestimated. Considering the worldwide trend toward increased NTM disease, the "diagnosis changed" rate may increase over time. Thus, when reporting the annual TB notification rate in Korea, the exclusion of "diagnosis changed" cases is desirable.
PMCID: PMC3884111  PMID: 24416054
Nontuberculous Mycobacteria; Tuberculosis; Diagnostic Errors; Incidence
15.  The health care burden of high grade chronic obstructive pulmonary disease in Korea: analysis of the Korean Health Insurance Review and Assessment Service data 
Patients with high grade chronic pulmonary obstructive disease (COPD) account for much of the COPD-related mortality and incur excessive financial burdens and medical care utilization. We aimed to determine the characteristics and medical care use of such patients using nationwide data from the Korean Health Insurance Review and Assessment Service in 2009.
Materials and methods
Patients with COPD were identified by searching with the International Classification of Diseases–10th Revision for those using medication. Patients with high grade COPD were selected based on their patterns of tertiary institute visits and medication use.
The numbers of patients with high grade COPD increased rapidly in Korea during the study period, and they showed a high prevalence of comorbid disease. The total medical costs were over three times higher in patients with high grade COPD compared with those without it ($3,744 versus $1,183; P < 0.001). Medication costs comprised the largest portion of medical cost, but most impact came from hospitalization and exacerbation in both groups of patients. COPD grade and hospitalization in the previous year were the major factors affecting medical costs and days of utilizing health care resources.
Patients with high grade COPD impose a high economic burden on the health care system in Korea. Prevention of progression to high grade COPD is important, both clinically and economically.
PMCID: PMC3838475  PMID: 24277985
COPD; population characteristics; health care utilization; medical cost
16.  Association between chronic obstructive pulmonary disease and gastroesophageal reflux disease: a national cross-sectional cohort study 
Gastroesophageal reflux disease (GERD) is one of the most common causes of chronic cough and a potential risk factor for exacerbation of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the prevalence and risk factors of GERD in patients with COPD and association between GERD and COPD exacerbation.
Data were collected from the National Health Insurance Database of Korea. The subjects were 40 years old and older, who had COPD as primary or secondary diagnosis codes and utilized health care resource to receive prescriptions of COPD medication at least twice in 2009. Univariate logistic regression was performed to understand the relationship between COPD and GERD, and multiple logistic regression analysis was performed with adjustment for several confounding factors.
The prevalence of GERD in COPD patients was 28% (39,987/141,057). Old age, female gender, medical aid insurance type, hospitalization, and emergency room (ER) visit were associated with GERD. Most of COPD medications except inhaled muscarinic antagonists were associated with GERD. The logistic regression analysis showed that the presence of GERD was associated with increased risk of hospitalization (OR 1.54, CI 1.50 to 1.58, p<0.001) and frequent ER visits (OR 1.55, CI 1.48 to 1.62, p<0.001).
The prevalence of GERD in patients with COPD was high. Old age, female gender, medical aid insurance type, and many COPD medications except inhaled muscarinic antagonists were associated with GERD. The presence of GERD was associated with COPD exacerbation.
PMCID: PMC3750392  PMID: 23927016
Gastroesophageal reflux; Obstructive lung disease; Prevalence; Exacerbation; Anticholinergic
17.  Systematic Review and Meta-Analysis of Pulmonary Hypertension Specific Therapy for Exercise Capacity in Chronic Obstructive Pulmonary Disease 
Journal of Korean Medical Science  2013;28(8):1200-1206.
Some patients with chronic obstructive pulmonary disease (COPD) have pulmonary hypertension (PH) that adversely affects survival. We performed a systematic review and meta-analysis to assess whether PH-specific therapies have an effect for stable COPD. Data sources were Medline, EMBASE, Cochrane Central Register of Controlled Trials, Korea med and references from relevant publications. Randomized prospective trials that compared PH specific therapy in COPD for more than 6 weeks with placebo were included. The outcomes were the exercise capacity and adverse events. Four randomized controlled trials involving 109 subjects were included in the analysis. Two trials involved bosentan, one sildenafil and one beraprost. The studies varied in duration of treatment from 3 to 18 months. In a pooled analysis of four trials, exercise-capacity was not significantly improved with PH-specific treatment for COPD (risk ratio, -5.1; 95% CI, -13.0 to 2.8). COPD with overt PH significantly improved the exercise capacity (mean difference, 111.6; 95% CI, 63.3 to 159.9) but COPD with PH unknown did not (mean difference, 26.6; 95% CI, -24.3 to 77.5). There was no significant difference in hypoxemia (mean difference, 2.6; 95% CI, -3.7 to 8.8). PH specific treatments have a significant effect in improving exercise capacity in COPD with overt PH.
PMCID: PMC3744709  PMID: 23960448
COPD; Pulmonary Hypertension; Vasodilator; Exercise
18.  Chronic Obstructive Pulmonary Disease Assessment Test Can Predict Depression: A Prospective Multi-Center Study 
Journal of Korean Medical Science  2013;28(7):1048-1054.
This study was conducted to investigate the association between the chronic obstructive pulmonary disease (COPD) assessment test (CAT) and depression in COPD patients. The Korean versions of the CAT and patient health questionnaire-9 (PHQ-9) were used to assess COPD symptoms and depressive disorder, respectively. In total, 803 patients with COPD were enrolled from 32 hospitals and the prevalence of depression was 23.8%. The CAT score correlated well with the PHQ-9 score (r=0.631; P<0.001) and was significantly associated with the presence of depression (β±standard error, 0.452±0.020; P<0.001). There was a tendency toward increasing severity of depression in patients with higher CAT scores. By assessment groups based on the 2011 Global Initiative for Chronic Obstructive Lung Disease guidelines, the prevalence of depression was affected more by current symptoms than by airway limitation. The area under the receiver operating characteristic curve for the CAT was 0.849 for predicting depression, and CAT scores ≥21 had the highest accuracy rate (80.6%). Among the eight CAT items, energy score showed the best correlation and highest power of discrimination. CAT scores are significantly associated with the presence of depression and have good performance for predicting depression in COPD patients.
PMCID: PMC3708076  PMID: 23853488
Pulmonary Disease, Chronic Obstructive; COPD Assessment Test; Depression
19.  Effects of Home-Based Pulmonary Rehabilitation with a Metronome-Guided Walking Pace in Chronic Obstructive Pulmonary Disease 
Journal of Korean Medical Science  2013;28(5):738-743.
Despite documented efficacy and recommendations, pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) has been underutilized. Home-based PR was proposed as an alternative, but there were limited data. The adequate exercise intensity was also a crucial issue. The aim of this study was to investigate the effects of home-based PR with a metronome-guided walking pace on functional exercise capacity and health-related quality of life (HRQOL) in COPD. The subjects participated in a 12-week home-based PR program. Exercise intensity was initially determined by cardiopulmonary exercise test, and was readjusted (the interval of metronome beeps was reset) according to submaximal endurance test. Six-minute walk test, pulmonary function test, cardiopulmonary exercise test, and St. George's Respiratory Questionnaire (SGRQ) were done before and after the 12-week program, and at 6 months after completion of rehabilitation. Thirty-three patients participated in the program. Six-minute walking distance was significantly increased (48.8 m; P = 0.017) and the SGRQ score was also improved (-15; P < 0.001) over the six-month follow-up period after rehabilitation. There were no significant differences in pulmonary function and peak exercise parameters. We developed an effective home-based PR program with a metronome-guided walking pace for COPD patients. This rehabilitation program may improve functional exercise capacity and HRQOL.
PMCID: PMC3653087  PMID: 23678266
Pulmonary Disease, Chronic Obstructive; Rehabilitation; Exercise Test; Quality of Life
20.  Diseases Concomitant With Asthma in Middle-Aged and Elderly Subjects in Korea: A Population-Based Study 
Asthma is prevalent in many countries. Few studies have investigated the association between asthma and concomitant diseases. We retrospectively analyzed the fourth Korean National Health and Nutrition Survey database, performed in 2008 using nationwide stratified random sampling to obtain a representative cohort of the Korean population.
We evaluated the association between both self-reported ever-asthmatics and wheezers and concomitant diseases such as arthritis, hypertension, gastrointestinal (GI) ulcers, dyslipidemia, diabetes mellitus, rhinitis, depression, stroke, and obesity in subjects aged ≥40 years. A multivariate analysis was performed to identify concomitant diseases independently associated with asthma, after adjustment for age, gender, income, cigarette smoking, and other chronic diseases.
Of the total of 4,445 subjects, 2,596 (58.4%) were female and the mean age was 58.3 years. Of the 4,445 subjects, 195 (4.4%) had been diagnosed with asthma at some point, and 444 (10%) were wheezers. Multivariate analysis showed that arthritis (odds ratio [OR] 1.74, 95% confidence interval [CI] 1.26-2.42), rhinitis (OR 1.78, 95% CI 1.14-2.78), depression (OR 1.45, 95% CI 1.05-2.07), and obesity (OR 1.61, 95% CI 1.08-2.40) were significantly associated with self-reported ever-asthma, and arthritis (OR 1.50, 95% CI 1.19-1.909), hypertension (OR 1.34, 95% CI 1.07-1.67), GI ulcers (OR 1.48, 95% CI 1.05-2.08), rhinitis (OR 1.60, 95% CI 1.16-2.19), depression (OR 1.94, 95% CI 1.51-2.48), and obesity (OR 1.56, 95% CI 1.17-2.09) were significantly associated with wheezers.
These findings indicate that arthritis, rhinitis, depression, and obesity may be associated with both self-reported ever asthma and wheezers in the Korean population.
PMCID: PMC3529224  PMID: 23277874
Asthma; arthritis; rhinitis; depression; obesity
21.  Comorbidities of Chronic Obstructive Pulmonary Disease in Koreans: A Population-Based Study 
Journal of Korean Medical Science  2012;27(8):901-906.
Chronic obstructive pulmonary disease (COPD) includes pulmonary components with increased comorbidity rates, as well as being a systemic disease. Comorbidities may frequently occur in COPD patients over 40 yr old. We report the comorbidities of patients with COPD, diagnosed by spirometry, in a population-based epidemiologic survey in Korea. Data were derived from the fourth Korean Health and Nutrition Examination Survey in 2008, a stratified multistage clustered probability design survey of a sample representing the entire population of Korea. Results of spirometry and various health-related questionnaires were analyzed in 2,177 subjects aged ≥ 40 yr. The prevalence of COPD (FEV1/FVC < 0.7) in subjects ≥ 40 yr of age was 14.1%. Multivariate analysis showed that underweight (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.05-8.98), coronary heart disease (OR, 0.43; 95% CI, 0.20-0.93) and dyslipidemia (OR, 0.61; 95% CI, 0.45-0.82) were significantly associated with COPD, whereas allergic rhinitis, anemia, arthritis, chronic renal failure, depression, diabetes mellitus, hypertension, gastrointestinal ulcer, and osteoporosis were not. Underweight might be more prevalent but coronary heart disease and dyslipidemia are less prevalent in Koreans with than without COPD in population setting.
PMCID: PMC3410238  PMID: 22876057
Chronic Obstructive Pulmonary Disease; Comorbidity; Population-Based Survey
22.  Tat-Mediated p66shc Transduction Decreased Phosphorylation of Endothelial Nitric Oxide Synthase in Endothelial Cells 
We evaluated the role of Tat-mediated p66shc transduction on the activation of endothelial nitric oxide synthase in cultured mouse endothelial cells. To construct the Tat-p66shc fusion protein, human full length p66shc cDNA was fused with the Tat-protein transduction domain. Transduction of TAT-p66shc showed a concentration- and time-dependent manner in endothelial cells. Tat-mediated p66shc transduction showed increased hydrogen peroxide and superoxide production, compared with Tat-p66shc (S/A), serine 36 residue mutant of p66shc. Tat-mediated p66shc transduction decreased endothelial nitric oxide synthase phosphorylation in endothelial cells. Furthermore, Tat-mediated p66shc transduction augmented TNF-α-induced p38 MAPK phosphorylation in endothelial cells. These results suggest that Tat-mediated p66shc transduction efficiently inhibited endothelial nitric oxide synthase phosphorylation in endothelial cells.
PMCID: PMC3394923  PMID: 22802702
p66shc; Tat-mediated transduction; Endothelial nitric oxide synthase; Superoxide; Endothelial cells
23.  Validity and Reliability of CAT and Dyspnea-12 in Bronchiectasis and Tuberculous Destroyed Lung 
The objective of this study was to assess the validity and reliability of the Korean version of chronic obstructive pulmonary disease assessment test (CAT) and Dyspnea-12 Questionnaire for patients with bronchiectasis or tuberculous destroyed lung.
For 62 bronchiectasis patients and 37 tuberculous destroyed lung patients, 3 questionnaires including St. George's Respiratory Questionnaires (SGRQ), CAT, and Dyspnea-12 were obtained, in addition to spirometric measurements. To assess the validity of CAT and Dyspnea-12, correlation with SGRQ was evaluated. To assess the reliability of CAT and Dyspnea-12, Cronbach's α coefficient was calculated.
The mean ages of the patients were 60.7±8.3 years in bronchiectasis and 64.4±9.3 years in tuberculous destroyed lung. 46.8% and 54.1% were male, respectively. The SGRQ score was correlated with the score of the Korean version of CAT (r=0.72, p<0.0001) and Dyspnea-12 (r=0.67, p<0.0001) in bronchiectasis patients. The SGRQ score was correlated with the score of CAT (r=0.86, p<0.0001) and Dyspnea-12 (r=0.80, p<0.0001) in tuberculous destroyed lung patients. The Cronbach's α coefficient for the CAT and Dyspnea-12 were 0.84 and 0.90 in bronchiectasis, and 0.88 and 0.94 in tuberculous destroyed lung, respectively.
We found that Korean version of CAT and Dyspnea-12 are valid and reliable in patients with tuberculous destroyed lung and bronchiectasis.
PMCID: PMC3475455  PMID: 23101012
Dyspnea; Severity of Illness Index; Questionnaires; Validation Studies; Bronchiectasis; Tuberculosis
24.  Increasing Trend of Isolation of Non-Tuberculous Mycobacteria in a Tertiary University Hospital in South Korea 
The isolation of non-tuberculous mycobacteria (NTM) has been increasing in South Korea. To date, however, the cause of this increase has not been determined, and it remains unclear whether the use of liquid media has contributed to this increase. The aim of this study was to evaluate the factors associated with NTM isolation and the impact of liquid media on NTM culture.
Mycobacterial smear/culture results of respiratory specimens (sputum and bronchial aspirates), obtained during the years 2002, 2005, and 2010, were retrieved and analyzed retrospectively.
During the years 2002, 2005, and 2010, 83,096 sputum specimens were collected from 31,104 patients, and were cultured for mycobacteria, using solid media only in the 2002 and 2005 specimens and both solid and liquid media in the 2010. Of these, 3,516 (4.2%) specimens were smear-positive for acid-fast bacilli (AFB). The annual rate of NTM among positive culture specimens increased from 21% in 2002 to 57.8% in 2010 (p<0.001), as did the proportion of NTM, among AFB smear- and culture-positive specimens, from 12.2% in 2002 to 45.2% in 2010 (p<0.001). In 2010, the NTM culture rate was higher in the liquid than in the solid media (13.9% vs. 8.4%, p<0.001). The NTM rate among AFB-positive specimens was higher in patients aged >50 than ≤50 years.
The rate of NTM isolation has steadily been increasing at the hospital in South Korea, likely due in part to the use of liquid media for the culture.
PMCID: PMC3475469  PMID: 23101005
Nontuberculous Mycobacteria; Culture Media; Sputum; Republic of Korea
25.  Comparison of Clinico-Physiologic and CT Imaging Risk Factors for COPD Exacerbation 
Journal of Korean Medical Science  2011;26(12):1606-1612.
To date, clinico-physiologic indices have not been compared with quantitative CT imaging indices in determining the risk of chronic obstructive pulmonary disease (COPD) exacerbation. We therefore compared clinico-physiologic and CT imaging indices as risk factors for COPD exacerbation in patients with COPD. We retrospectively analyzed 260 COPD patients from pulmonary clinics at 11 hospitals in Korea from June 2005 to November 2009 and followed-up for at least one year. At the time of enrollment, none of these patients had COPD exacerbations for at least 2 months. All underwent clinico-physiologic and radiological evaluation for risk factors of COPD exacerbation. After 1 yr, 106 of the 260 patients had at least one exacerbation of COPD. Multiple logistic regression analysis showed that old age, high Charlson Index, and low FEV1 were significant in a clinico-physiologic model, with C-statistics of 0.69, and that increased age and emphysema index were significant in a radiologic model, with C-statistics of 0.64. The difference between the two models was statistically significant (P = 0.04 by bootstrap analysis). Combinations of clinico-physiologic risk factors may be better than those of imaging risk factors in predicting COPD exacerbation.
PMCID: PMC3230021  PMID: 22147998
Pulmonary Disease, Chronic Obstructive; Exacerbation; Risk Factors; Computed Tomography

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