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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Vasorelaxing Activity of Ulmus davidiana Ethanol Extracts in Rats: Activation of Endothelial Nitric Oxide Synthase 
Ulmus davidiana var. japonica Rehder (Urticales: Ulmaceae) (UD) is a tree widespread in northeast Asia. It is traditionally used for anticancer and anti-inflammatory therapy. The present study investigated the effect of an ethanol extract of UD on vascular tension and its underlying mechanism in rats. The dried root bark of UD was ground and extracted with 80% ethanol. The prepared UD extract was used in further analysis. The effect of UD on the cell viability, vasoreactivity and hemodynamics were investigated using propidium iodide staining in cultured cells, isometric tension recording and blood pressure analysis, respectively. Low dose of UD (10~100µg/ml) did not affect endothelial cell viability, but high dose of UD reduced cell viability. UD induced vasorelaxation in the range of 0.1~10µg/ml with an ED50 value of 2µg/ml. UD-induced vasorelaxation was completely abolished by removal of the endothelium or by pre-treatment with L-NAME, an inhibitor of nitric oxide synthase. UD inhibited calcium influx induced by phenylephrine and high K+ and also completely abolished the effect of L-NAME. Intravenous injection of UD extracts (10~100 mg/kg) decreased arterial and ventricular pressure in a dose-dependent manner. Moreover, UD extracts reduced the ventricular contractility (+dP/dt) in anesthetized rats. However, UD-induced hypotensive actions were minimized in L-NAME-treated rats. Taken together, out results showed that UD induced vasorelaxation and has antihypertensive properties, which may be due the activation of nitric oxide synthase in endothelium.
PMCID: PMC3282221  PMID: 22359471
Ulmus davidiana var. japonica; Endothelial nitric oxide synthase; Vasorelaxation; Blood pressure; Ventricular contractility
14.  Usefulness of Quantitative Endotracheal Aspirate Cultures in Intensive Care Unit Patients with Suspected Pneumonia 
Journal of Korean Medical Science  2011;26(7):865-869.
It is difficult to differentiate pathogens responsible for pneumonia or colonization in patients with an endotracheal tube or in patients that have undergone tracheostomy. We evaluated the clinical usefulness of quantitative endotracheal aspirates cultures and sought to determine the result threshold level for positivity. The authors performed this retrospective cohort study between December 1, 2004 and January 31, 2006. Forty-five suspected pneumonia patients admitted to an intensive care unit (ICU) with quantitative bronchoalveolar lavage (BAL) and endotracheal aspirate (EA) culture results were enrolled. Using a threshold of 105 cfu/mL, 10 of the 45 (22.2%) quantitative EA cultures were positive, as compared with 7 (15.6%) BAL cultures. When BAL culture findings were used as the reference, the sensitivity and specificity of quantitative EA cultures were 85.7% and 89.5%, respectively, at a threshold of 105 cfu/mL, and 85.7% and 94.7%, respectively, at a threshold of 106 cfu/mL. Of the 10 EA culture positive patients, 2 patients with a result of -105 cfu/mL were BAL culture negative. The quantitative EA culture is a useful non-invasive tool for the diagnosis of pneumonia pathogens. It is suggested that a threshold level of 106 cfu/mL is appropriate.
PMCID: PMC3124714  PMID: 21738337
Quantitative Culture; Endotracheal Aspirate; Pneumonia
15.  Hypoxemia and Arrhythmia during Daily Activities and Six-minute Walk Test in Fibrotic Interstitial Lung Diseases 
Journal of Korean Medical Science  2011;26(3):372-378.
We performed 24-hr monitoring of pulse oximetric saturation (SpO2) with ECG and six-minute walk test (6MWT) in 19 patients with fibrotic interstitial lung diseases (ILD) to investigate; 1) The frequency and severity of hypoxemia and dysrhythmia during daily activities and 6MWT, 2) safety of 6MWT, and 3) the parameters of 6MWT which can replace 24-hr continuous monitoring of SpO2 to predict hypoxemia during daily activities. All patients experienced waking hour hypoxemia, and eight of nineteen patients spent > 10% of waking hours in hypoxemic state. Most patients experienced frequent arrhythmia, mostly atrial premature contractions (APCs) and ventricular premature contractions (VPCs). There were significant correlation between the variables of 6MWT and hypoxemia during daily activities. All of the patients who desaturated below 80% before 300 meters spent more than 10% of waking hour in hypoxemia (P = 0.018). In contrast to waking hour hypoxemia, SpO2 did not drop significantly during sleep except in the patients whose daytime resting SpO2 was already low. In conclusion, patients with fibrotic ILD showed significant period of hypoxemia during daily activities and frequent VPCs and APCs. Six-minute walk test is a useful surrogate marker of waking hour hypoxemia and seems to be safe without continuous monitoring of SpO2.
PMCID: PMC3051084  PMID: 21394305
Arrhythmias, Cardiac; Anoxia; Lung Diseases, Interstitial; Six-Minute Walk Test
16.  The Risk of Obstructive Lung Disease by Previous Pulmonary Tuberculosis in a Country with Intermediate Burden of Tuberculosis 
Journal of Korean Medical Science  2011;26(2):268-273.
We evaluated the effects of previous pulmonary tuberculosis (TB) on the risk of obstructive lung disease. We analyzed population-based, the Second Korea National Health and Nutrition Examination Survey 2001. Participants underwent chest X-rays (CXR) and spirometry, and qualified radiologists interpreted the presence of TB lesion independently. A total of 3,687 underwent acceptable spirometry and CXR. Two hundreds and ninty four subjects had evidence of previous TB on CXR with no subjects having evidence of active disease. Evidence of previous TB on CXR were independently associated with airflow obstruction (adjusted odds ratios [OR] = 2.56 [95% CI 1.84-3.56]) after adjustment for sex, age and smoking history. Previous TB was still a risk factor (adjusted OR = 3.13 [95% CI 1.86-5.29]) with exclusion of ever smokers or subjects with advanced lesion on CXR. Among never-smokers, the proportion of subjects with previous TB on CXR increased as obstructive lung disease became more severe. Previous TB is an independent risk factor for obstructive lung disease, even if the lesion is minimal and TB can be an important cause of obstructive lung disease in never-smokers. Effort on prevention and control of TB is crucial in reduction of obstructive lung disease, especially in countries with more than intermediate burden of TB.
PMCID: PMC3031013  PMID: 21286020
Tuberculosis; Lung Diseases, Obstructive
17.  Downregulation of NFAT2 promotes melanogenesis in B16 melanoma cells 
Anatomy & Cell Biology  2010;43(4):303-309.
Nuclear factor of activated T-cells (NFAT) proteins are, calcium-regulated transcription factors, key regulator of stimulation-dependent gene activation. In our microarray analysis for the genes expressed in human black and white hairs, NFAT2 was significantly upregulated in the white hair, compared to the black hair. The aim of this study was to investigate functional role of NFAT2 in melanogenesis. Western blot analysis was performed to investigate the expression of NFAT2 protein in B16 melanoma cells. Our data showed that NFAT2 expression was increased in the hypopigmented B16 cells, while tyrosinase and MITF expression was decreased. To investigate the potential role of NFAT2, the recombinant adenovirus expressing microRNA specific for NFAT2 was transduced into the cultured B16 melanoma cells. Consistently, inhibition of NFAT2 enhanced tyrosinase activity and melanin content. Moreover, cyclosporine A, which is known as a calcineurin inhibitor blocking NFAT activation, enhanced tyrosinase activity and melanin content. These data suggest that NFAT2 may play an important role in regulation of melanogenesis in melanocyte.
PMCID: PMC3026182  PMID: 21267404
Melanogenesis; Melanocyte; B16 melanoma cells; NFAT2; Cyclosprorin A
18.  The Relationship between the Presence of Chromosomal Instability and Prognosis of Squamous Cell Carcinoma of the Lung: Fluorescence in situ Hybridization Analysis of Paraffin-embedded Tissue from 47 Korean Patients 
Journal of Korean Medical Science  2010;25(6):863-867.
To evaluate the prognostic importance of chromosomal instability (CIN) in squamous cell carcinoma (SCC) of the lung, the relationship between CIN detected by fluorescence in situ hybridization (FISH) and survival in SCC patients was examined. Forty-seven surgical specimens of lung SCC were analyzed. To identify tumors with CIN, p16 and multi-target DNA FISH assays for c-myc, chromosome 6, EGFR, and chromosome 5 (LAVysion, Vysis) were performed on nuclei extracted from paraffin-embedded tumor tissues. Survival rates were compared in terms of age, T factor, N factor, CIN, and smoking status. A sample was defined as CIN-positive if at least four of the five chromosomes were positive. Among the 47 specimens, 9 (19%) were CIN-positive. The overall survival rate was 66%. Overall survival rates were estimated as 33.3% for CIN-positive patients and 76.7% for CIN-negative patients (Hazard ratio 3.47; 95% Confidence interval, 1.25-9.67; P=0.017). In multivariate analysis, the presence of CIN was a predictive factor for survival. CIN-positive based on FISH can be prognostic factor of lung SCC.
PMCID: PMC2877246  PMID: 20514306
Chromosomal Instability; In Situ Hybridization, Fluorescence; Lung Neoplasms; Carcinoma, Squamous Cell
19.  Redox Factor-1 Inhibits Cyclooxygenase-2 Expression via Inhibiting of p38 MAPK in the A549 Cells 
In this study, we evaluated the role of apurinic/apyrimidinic endonuclease1/redox factor-1 (Ref-1) on the tumor necrosis factor-α (TNF-α) induced cyclooxygenase-2 (COX-2) expression using A549 lung adenocarcinoma cells. TNF-α induced the expression of COX-2 in A549 cells, but did not induce BEAS-2B expression. The expression of COX-2 in A549 cells was TNF-α dose-dependent (5~100 ng/ml). TNF-α-stimulated A549 cells evidenced increased Ref-1 expression in a dose-dependent manner. The adenoviral transfection of cells with AdRef-1 inhibited TNF-α-induced COX-2 expression relative to that seen in the control cells (Adβgal). Pretreatment with 10 µM of SB203580 suppressed TNF-α-induced COX-2 expression, thereby suggesting that p38 MAPK might be involved in COX-2 expression in A549 cells. The phosphorylation of p38 MAPK was increased significantly after 5 minutes of treatment with TNF-α, reaching a maximum level at 10 min which persisted for up to 60 min. However, p38MAPK phosphorylation was markedly suppressed in the Ref-1-overexpressed A549 cells. Taken together, our results appear to indicate that Ref-1 negatively regulates COX-2 expression in response to cytokine stimulation via the inhibition of p38 MAPK phosphorylation. In the lung cancer cell lines, Ref-1 may be involved as an important negative regulator of inflammatory gene expression.
PMCID: PMC2902804  PMID: 20631885
Redox factor-1; Cyclooxygenase-2; A549; Lung cancer; p38 MAPK
20.  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
21.  Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract 
Experimental & Molecular Medicine  2009;41(4):277-287.
Matrix metalloproteinase-9 (MMP-9) may play an important role in emphysematous change in chronic obstructive pulmonary disease (COPD), one of the leading causes of mortality and morbidity worldwide. We previously reported that simvastatin, an inhibitor of HMG-CoA reductase, attenuates emphysematous change and MMP-9 induction in the lungs of rats exposed to cigarette smoke. However, it remained uncertain how cigarette smoke induced MMP-9 and how simvastatin inhibited cigarette smoke-induced MMP-9 expression in alveolar macrophages (AMs), a major source of MMP-9 in the lungs of COPD patients. Presently, we examined the related signaling for MMP-9 induction and the inhibitory mechanism of simvastatin on MMP-9 induction in AMs exposed to cigarette smoke extract (CSE). In isolated rat AMs, CSE induced MMP-9 expression and phosphorylation of ERK and Akt. A chemical inhibitor of MEK1/2 or PI3K reduced phosphorylation of ERK or Akt, respectively, and also inhibited CSE-mediated MMP-9 induction. Simvastatin reduced CSE-mediated MMP-9 induction, and simvastatin-mediated inhibition was reversed by farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP). Similar to simvastatin, inhibition of FPP transferase or GGPP transferase suppressed CSE-mediated MMP-9 induction. Simvastatin attenuated CSE-mediated activation of RAS and phosphorylation of ERK, Akt, p65, IκB, and nuclear AP-1 or NF-κB activity. Taken together, these results suggest that simvastatin may inhibit CSE-mediated MMP-9 induction, primarily by blocking prenylation of RAS in the signaling pathways, in which Raf-MEK-ERK, PI3K/Akt, AP-1, and IκB-NF-κB are involved.
PMCID: PMC2679231  PMID: 19299917
macrophages, alveolar; matrix metalloproteinases-9; pulmonary disease, chronic obstructive; pulmonary emphysema; simvastatin; smoking
22.  Beneficial and Adverse Effects of Bosentan Treatment in Korean Patients With Pulmonary Artery Hypertension 
Korean Circulation Journal  2009;39(3):105-110.
Background and Objectives
The purpose of this study was to investigate 1) the beneficial effect of bosentan treatment (125 mg twice daily) on exercise capacity and echocardiographic variables and 2) the profiles and frequency of adverse events in Korean patients with World Health Organization (WHO) class III or IV pulmonary artery hypertension (PAH).
Subjects and Methods
Twelve patients who received bosentan treatment were investigated in an open label manner. One patient was excluded in the final analyses due to a prohibited concomitant medication. A 6-minute walk test and echocardiography were performed at baseline and after 12 weeks of treatment.
The administration of bosentan for 12 weeks resulted in a significant improvement in exercise capacity (measured with the 6-minute walking distance), WHO functional capacity, and in echocardiographic variables. Bosentan treatment was associated with a decrease in the maximal tricuspid regurgitation jet velocity {from 4.7 m/sec (95% confidence interval, 3.89-5.45) at baseline to 4.4 m/sec (95% confidence interval, 3.61-5.1) at 12 weeks, p=0.03} and systolic pulmonary arterial pressure {from 105 mmHg (95% confidence interval, 74.4-135.6) at baseline to 93 mmHg (95% confidence interval, 66.3-120.1) at 12 weeks, p=0.04}. Treatment with bosentan at a dose of 125 mg twice a day was not associated with life-threatening side effects, although a higher incidence of elevated liver enzymes compared to previous studies was noted.
Bosentan at a dose of 125 mg twice daily is considered a clinically optimal, safe dose and can be used as a valuable treatment option in Korean PAH patients with WHO functional capacity III or IV, though close monitoring of liver function is required.
PMCID: PMC2771800  PMID: 19949596
Hypertension, pulmonary; Bosentan; Adverse effects
23.  Predisposition of genetic disease by modestly decreased expression of GCH1 mutant allele 
Experimental & Molecular Medicine  2008;40(3):271-275.
Recently it was shown that single nucleotide polymorphisms (SNPs) can explain individual variation because of the small changes of the gene expression level and that the 50% decreased expression of an allele might even lead to predisposition to cancer. In this study, we found that a decreased expression of an allele might cause predisposition to genetic disease. Dopa responsive dystonia (DRD) is a dominant disease caused by mutations in GCH1 gene. The sequence analysis of the GCH1 in a patient with typical DRD symptoms revealed two novel missense mutations instead of a single dominant mutation. Family members with either of the mutations did not have any symptoms of DRD. The expression level of a R198W mutant allele decreased to about 50%, suggesting that modestly decreased expression caused by an SNP should lead to predisposition of a genetic disease in susceptible individuals.
PMCID: PMC2679294  PMID: 18587264
dystonic disorders; germ-line mutation; point mutation; polymorphism, single nucleotide
24.  The Clinical Efficacy of GOCA Scoring System in Patients with Acute Respiratory Distress Syndrome 
Journal of Korean Medical Science  2008;23(3):383-389.
To explore the following hypotheses: 1) Gas exchange, Organ failure, Cause, Associated disease (GOCA) score, which reflects both general health and the severity of lung injury, would be a better mortality predictor of acute respiratory distress syndrome (ARDS) than acute physiology and chronic health evaluation (APACHE II) or simplified acute physiology score (SAPS II), which are not specific to lung injury, and lung injury score (LIS) that focuses on the lung injury; 2) the performance of APACHE II and SAPS II will be improved when reinforced by LIS, we retrospectively analyzed ARDS patients (N=158) admitted to a medical intensive care unit for five years. The overall mortality of the ARDS patients was 53.2%. Calibrations for all models were good. The area under the curve of (AUC) of LIS (0.622) was significantly less than those of APACHE II (0.743) and SAPS II (0.753). The AUC of GOCA (0.703) was not better than those of APACHE II and SAPS II. The AUCs of APACHE II and SAPS II tended to further increase when reinforced by LIS. In conclusion, GOCA was not superior to APACHE II or SAPS II. The performance of the APACHE II or SAPS II tended to improve when combining a general scoring system with a scoring system that focused on the severity of lung injury.
PMCID: PMC2526539  PMID: 18583871
Respiratory Distress Syndrome, Adult; APACHE; SAPS II; GOCA; LIS; Severity Scoring System; Mortality; Patients
25.  Diagnostic utility of the soluble triggering receptor expressed on myeloid cells-1 in bronchoalveolar lavage fluid from patients with bilateral lung infiltrates 
Critical Care  2008;12(1):R6.
Differential diagnosis of patients with bilateral lung infiltrates remains a difficult problem for intensive care clinicians. Here we evaluate the diagnostic role of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in bronchoalveolar lavage (BAL) specimens from patients with bilateral lung infiltrates.
We conducted a prospective observational study on 80 patients with bilateral lung infiltrates with clinical suspicion of infectious pneumonia. Patients were categorized into three groups: bacterial or fungal infection, intracellular or viral infection, and noninfectious inflammatory disease. sTREM-1 concentrations were measured, and BAL fluid and Clinical Pulmonary Infection Score (CPIS) were analyzed.
The sTREM-1 concentration was significantly increased in patients with bacterial or fungal pneumonia (n = 29, 521.2 ± 94.7 pg/ml), compared with that in patients with viral pneumonia, atypical pneumonia or tuberculosis (n = 14, 92.9 ± 20.0 pg/ml) or noninfectious inflammatory disease (n = 37, 92.8 ± 10.7 pg/ml). The concentration of sTREM-1 in BAL fluid, but not CPIS, was an independent predictor of bacterial or fungal pneumonia, and a cutoff value of more than 184 pg/ml yielded a diagnostic sensitivity of 86% and a specificity of 90%.
The sTREM-1 level in BAL fluid from patients with bilateral lung infiltrates is a potential marker for the differential diagnosis of pneumonia due to extracellular bacteria.
PMCID: PMC2374623  PMID: 18205941

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