Serum bilirubin level is associated with exercise capacity and quality of life in chronic obstructive pulmonary disease

BACKGROUND: Bilirubin has antioxidant properties against chronic respiratory diseases. However, previous studies are limited by acquisition of serum bilirubin level at one time point and its analysis with clinical parameters. We evaluated the association of serum bilirubin levels with various clinical outcomes of chronic obstructive pulmonary disease (COPD) in Korean Obstructive Lung Disease (KOLD) cohort. METHODS: We included 535 patients with COPD from the KOLD cohort. Serum bilirubin levels and various clinical parameters, such as lung function, 6-min walking (6 MW) distance, quality of life (QoL), and exacerbation, were evaluated annually; their association was analyzed using generalized estimating equations and the linear mixed model. RESULTS: Among 535 patients, 345 (64.5%) and 190 (35.5%) were categorized into Global Initiative for Chronic Obstructive Lung Disease (GOLD) I-II and GOLD III-IV groups, respectively. 6 MW distance was positively associated with serum bilirubin levels, especially in the GOLD I-II group (estimated mean = 41.5). Among QoL indexes, the COPD assessment test score was negatively associated with serum bilirubin levels only in the GOLD I-II group (estimated mean = - 2.8). Higher serum bilirubin levels were independently associated with a higher number of acute exacerbation in the GOLD III-IV group (estimated mean = 0.45, P = 0.001). Multivariate analysis revealed that lung function and mortality were not associated with serum bilirubin levels. CONCLUSIONS: Higher serum bilirubin levels were associated with a longer 6 MW distance and better QoL, especially in the GOLD I-II group, whereas they were related to a higher risk of acute exacerbation, especially in the GOLD III-IV group. Bilirubin levels may represent various conditions in COPD.ope

bleomycin 으로 유도된 폐 섬유화 쥐 모델에서 EphrinA2-EphrinA1 신호 전달 체계의 조절을 통한 all-trans retinoic acid의 항섬유화 효과

Dept. of Medicine/박사Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and usually lethal lung disease of unknown pathophysiology. All-trans retinoic acid (ATRA) is a biologically active metabolite of vitamin A, and is known to affect cell differentiation, proliferation, and development. Eph-Ephrin signaling mediates various cellular processes including vasculogenesis, angiogenesis, cell migration, axon guidance, fluid homeostasis and repair after injury. Only a few studies about the effect of ATRA of pulmonary fibrosis have been reported. And the relationship between pulmonary fibrosis and ephrin type-A receptor 2 (EphA2) signaling remains unclear. Purpose: The aim of this study is to evaluation the role and related signal pathways of ATRA in the bleomycin-induced pulmonary fibrosis mouse model and whether the mechanism involves the regulation of pre-existing pathways such as and Eph-Ephrin, PI3k-Akt or Wnt/ß-catenin signaling pathway. Methods and Materials: A549 epithelial cells and CCD-11 Lu fibroblast were incubated and stimulated with or without ATRA, TGF-β1, and PI3K inhibitor, respectively. The levels of Smad2/3 and p-Smad2/3 were analyzed by western blotting. For animal models, we studied four experimental mice groups. There were PBS control group (PBS exposure), bleomycin + PBS group (PBS instillation after bleomycin exposure), bleomycin + ATRA group (peritoneal ATRA injection after bleomycin exposure), bleomycin + EphA2 monoclonal antibody group (EphA2 mAb instillation posttreatment after bleomycin exposure). On day 21, eight mice of each group were sacrificed. The cell counts and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology, hydroxyproline assay, and the expression of several signal pathway proteins including EphA2-EphrinA1, PI3K-Akt, Wnt/ß-catenin, and cytokine levels were compared among the groups. Results: In this study, ATRA attenuates PI3K/Akt signaling in fibroblast. We report that bleomycin exposure significantly upregulated EphA2 and EphrinA1 expression at day 21 after bleomycin exposure. ATRA posttreatment attenuated lung injury score and reduced protein concentration of BALF. The expression of EphA2, Ephrin, and PI3K 110γ protein was significantly increased after bleomycin instillation, and decreased after ATRA posttreatment. ATRA led to a decrease of IL-6 and TNF-α production in the bleomycin + ATRA group compared to the bleomycin + PBS group (all, P < 0.05). Inhibiting EphA2 receptor by intranasal EphA2 mAb instillation attenuated pulmonary fibrosis, reduced cell counts and protein concentration of BALF (all, P < 0.05). Furthermore, bleomycin exposure upregulated the expression of Wnt5a and PI3K, and inhibiting EphA2 receptor downregulated both of them. Conclusion: The present data suggest that ATRA attenuated bleomycin-induced pulmonary fibrosis, and that it may regulate the EphA2-EphrinA1 signaling and PI3K dependent pathway. Furthermore, EphA2 antagonism attenuates the PI3K dependent pathway and Wnt/ß-catenin-independent pathway, and decreased pulmonary fibrosis. Therefore, ATRA and inhibitor for EphA2 may have a protective effect in bleomycin-induced pulmonary fibrosis. 배경: 특발성 폐섬유화증은 만성적, 비가역적으로 진행하며, 종종 치명적인 결과를 초래하는 폐 질환으로, 그 병태생리는 명확하게 알려져 있지 않다. All-trans retinoic acid (ATRA)는 비타민 A의 활성화된 대사물로, 세포의 분화와 증식, 발달과 관계되는 것으로 알려져 있다. 한편, Eph-Ephrin 신호 전달 체계는 혈관의 형성, 세포의 이동, 세액의 항상성 및 손상 후의 복구를 포함한 다양한 세포 과정을 매개한다. 폐섬유화에 대한 ATRA의 효과에 대하여 소수의 연구가 보고된 바 있으며, 폐섬유화외 EphA2 신호 전달 체계의 상관 관계에 대하여는 아직 명확하게 밝혀져 있지 않다. 목적: 본 연구에서는 bleomycin으로 유도된 폐섬유화 마우스 모델에서 ATRA 의 역할과, 그 메커니즘이 Eph-Ephrin, PI3K-Akt 혹은 Wnt/ß-catenin과 같은 기존에 존재하는 신호 전달 체계와 연관되는지를 밝히고자 하였다. 방법: 세포 실험에서 epithelial cell과 fibroblast를 ATRA, TGF-β1, 그리고 PI3K 억제제의 유무에 따라 배양하였다. 동물 실험은 대조군, bleomycin 그룹, ATRA 그룹, EphA2 monoclonal antibody 그룹의 4 그룹으로 나누어 진행하였다. 21일째에 각 그룹의 mice로부터 기관지폐포세척액을 획득하여 세포 수와 단백질 농도를 그룹별로 비교, 분석하였다. 또한 폐 조직을 얻어 각 그룹의 조직학적 변화를 비교하고, hydroxyproline assay, Eph...ope

Lysophosphatidylcholine Alleviates Acute Lung Injury by Regulating Neutrophil Motility and Neutrophil Extracellular Trap Formation

Sepsis is predominantly initiated by bacterial infection and can cause systemic inflammation, which frequently leads to rapid death of the patient. However, this acute systemic inflammatory response requires further investigation from the perspectives of clinical judgment criteria and early treatment strategies for the relief of symptoms. Lysophosphatidylcholine (LPC) 18:0 may relieve septic symptoms, but the relevant mechanism is not clearly understood. Therefore, we aimed to assess the effectiveness of LPC as a therapeutic treatment for acute inflammation in the lung induced by lipopolysaccharide in mice. Systemic inflammation of mice was induced by lipopolysaccharide (LPS) inoculation to investigate the role of LPC in the migration and the immune response of neutrophils during acute lung injury. By employing two-photon intravital imaging of the LPS-stimulated LysM-GFP mice and other in vitro and in vivo assays, we examined whether LPC alleviates the inflammatory effect of sepsis. We also tested the effect of LPC to human neutrophils from healthy control and sepsis patients. Our data showed that LPC treatment reduced the infiltration of innate immune cells into the lung. Specifically, LPC altered neutrophil migratory patterns and enhanced phagocytic efficacy in the damaged lung. Moreover, LPC treatment reduced the release of neutrophil extracellular trap (NET), which can damage tissue in the inflamed organ and exacerbate disease. It also reduced human neutrophil migration under inflammatory environment. Our results suggest that LPC can alleviate sepsis-induced lung inflammation by regulating the function of neutrophils. These findings provide evidence for the beneficial application of LPC treatment as a potential therapeutic strategy for sepsis.ope

Factors associated with stage of change in smoker in relation to smoking cessation based on the Korean National Health and Nutrition Examination Survey II-V

Despite a decrease in incidence, smoking remains the most serious public health problem worldwide. Identification of the factors contributing to changes in willingness to quit smoking may aid the development of strategies that encourage smoking cessation. Pooled cross-sectional data from 11,924 smokers from the Korean National Health and Nutrition Examination Survey II-V were analyzed. The stages of change in smoking cessation were categorized as pre-contemplation, contemplation, and preparation. Baseline characteristics, socioeconomic factors, quality of life, psychological status, and smoking-related factors were compared between groups. The smokers were grouped as follows: 32.4% pre-contemplation, 54.4% contemplation, and 13.1% preparation. The proportion of smokers in the pre-contemplation group decreased (from 37.4% to 28.4%) from 2001 to 2012, while the proportion in the preparation group increased (from 6.4% to 18.1%). Compared with the preparation group, after adjusting for confounding factors, the pre-contemplation group was older [≥65 years-old; odds ratio (OR) = 1.40], more often single (OR = 1.38), less educated (elementary school or lower; OR = 1.93), less physically active in terms of walking (OR = 1.38) or performing strengthening exercises (OR = 1.61), smoked more heavily (≥20 cigarettes per day; OR = 4.75), and had a lower prevalence of chronic disease (OR = 0.76). Moreover, smokers who had never received education on smoking cessation were less willing to quit than those who had (OR = 0.44). In Korean smokers, the stages of change for smoking cessation were associated with age, education, marital status, chronic diseases, physical activity, and participation in smoking cessation programs.ope

Incidence and risk of chronic obstructive pulmonary disease in a Korean community-based cohort

Purpose: COPD is a leading cause of morbidity and mortality. However, few studies have used spirometry to investigate its incidence, especially in Asia. In the present study, we analyzed the incidence and risk factors of COPD using a community cohort database in Korea. Patients and methods: The study included 6,517 subjects aged 40-69 years from the Ansung-Ansan cohort database I-III (2001-2006). We calculated the crude incidence rate and the standardized incidence rate corrected for the Korean general population and the world population with COPD. We also determined the relative risks (RRs) for incident COPD and the attributable risks. Results: In total, 329 new COPD cases were diagnosed during follow-up. The overall crude incidence rate per 100,000 person-years was 1,447. The standardized incidence rate corrected for the Korean general population was 1,550; this value was higher in men and increased with increasing age. Risk factors for incident COPD were age >/=60 years (adjusted RR [aRR] =2.52 vs age /=20 pack-years; aRR =2.54 vs never smoker), and lowest income group (first quartile; aRR =2.03 vs fourth quartile). The adjusted attributable risk was highest for education level of high school or lower (44.9%), followed by smoking history (25.8%), income (22.9%), and sex (12.0%). Conclusion: In Korea, 15.5/1,000 people are diagnosed with COPD annually. The incidence rate increases with increasing age, heavier smoking, and decreasing income, with a higher rate in men than in women.ope

Development of a Pharmacokinetic Interaction Model for Co-administration of Simvastatin and Amlodipine

A model for drug interaction between amlodipine and simvastatin was developed using concentration data obtained from a multiple-dose study consisting of single- and co-administration of amlodipine and simvastatin conducted in healthy Koreans. Amlodipine concentrations were assumed to influence the clearance of simvastatin and simvastatin acid, which as well as the oral bioavailability was allowed to vary depending on genetic polymorphisms of metabolic enzymes. Covariate effects on drug concentrations were also considered. The developed model yielded a 46% increase in simvastatin bioavailability and a 13% decrease in simvastatin clearance when amlodipine 10 mg was co-administered. When CYP3A4/5 polymorphisms were assessed by a mixture model, extensive metabolizers yielded a decrease in simvastatin bioavailability of 81% and a decrease in simvastatin clearance by 4.6 times as compared to poor metabolizers. Sixty percent of the usual dose was the optimal simvastatin dose that can minimize the interaction with amlodipine 10 mg. Age and weight had significant effects on amlodipine concentrations. In conclusion, this study has quantitatively described the pharmacokinetic interaction between simvastatin and amlodipine using a modeling approach. Given that the two drugs are often prescribed together, the developed model is expected to contribute to more efficient and safer drug treatment when they are co-administered.ope

Soluble IL-2R Levels Predict in-Hospital Mortality in COVID-19 Patients with Respiratory Failure

Acute respiratory distress syndrome is the primary cause of death in patients with coronavirus disease 2019 (COVID-19) pneumonia. Our study aims to determine the association between serum markers and mortality in COVID-19 patients with respiratory failure. This retrospective study was conducted in a tertiary care hospital in South Korea. Forty-nine patients with COVID-19, who required high flow nasal cannulation or mechanical ventilation from February 2020 to April 2021, were included. Demographic and laboratory data were analyzed at baseline and on Day 7 of admission. We found that serum creatinine, troponin, procalcitonin, and soluble interleukin-2 receptor (sIL-2R) at baseline were more elevated in the non-survivor group, but were not associated with mechanical ventilator use on Day 7. Older age, PaO2/FiO2 ratio, lymphocyte and platelet counts, lactate dehydrogenase, IL-6, C-reactive protein, and sIL-2R on Day 7 were significantly associated with mortality. Delta sIL-2R (Day 7-Day 0) per standard deviation was significantly higher in the non-survivor group (adjusted hazard ratio 3.225, 95% confidence interval (CI) 1.151-9.037, p = 0.026). Therefore, sIL-2R could predict mortality in COVID-19 patients with respiratory failure. Its sustained elevation suggests a hyper-inflammatory state, and mirrors the severity of COVID-19 in patients with respiratory failure, thereby warranting further attention.ope

Human herpesvirus 8-negative effusion-based lymphoma with indolent clinical behavior in an elderly patient: A case report and literature review

Primary effusion lymphoma (PEL) is a B-cell non-Hodgkin's lymphoma that is usually characterized by lymphomatous effusions in the body cavity without any detectable tumor masses. According to the World Health Organization (WHO) schema for tumor classification, PEL is defined by the presence of human herpesvirus 8 (HHV8) in malignant lymphoid cells. However, a subset of effusion-based B-cell lymphoma is not HHV8-positive and exhibits different clinicopathological characteristics. The 2017 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues does not list HHV8-negative effusion-based lymphoma, which remains an underappreciated B-cell lymphoma, as an individual entity. The present study reports a case of this rare type of lymphoma with indolent clinical behavior in a 75-year-old male patient receiving only symptomatic treatment. Additionally, a review of similar cases reported in the English literature is presented.ope

Relationship between pulmonary function and bone mineral density in the Korean National Health and Nutrition Examination Survey

BACKGROUND/AIMS: Osteoporosis is common in chronic obstructive pulmonary disease (COPD) patients. The relationship between osteoporosis and COPD has been primarily reported in patients with moderate to severe COPD, but there is no report in the general population. The aim of this study is to investigate the relationship between bone mineral density (BMD) and lung function in the general Korean population. METHODS: This study was based on data acquired from the Fourth and Fifth Korea National Health and Nutrition Examination Surveys (KNHANES IV and V), conducted from 2008 to 2010. The study population included 4,501 subjects (aged ≥ 50 years) who underwent both spirometry and BMD. The study populations were divided into two groups by sex to correct for the effects of gender on BMD. All female participants were postmenopausal women. RESULTS: The BMD values of the femur neck, total femur, and L-spine tended to decrease with degree of airflow limitation in both genders. To correct confounding factors, data were analyzed and adjusted for age, body mass index, fat free mass index, body fat percentage, smoking amount, parathyroid hormone levels, daily calcium and phosphorus intake, and alkaline phosphatase (ALP) levels. While the BMD of the femur neck, total femur, and L-spine was reduced significantly as age and ALP increased, the correlation between airway obstruction and BMD of all regions disappeared in both genders. CONCLUSIONS: In the general population aged 50 years and older, diminution of BMD is not associated with airway obstruction. Further investigation along other factors is needed to determine the possible role of pulmonary function and BMD.ope

Longitudinal decline in lung function: a community-based cohort study in Korea

Progressive decline in lung function is the hallmark of chronic obstructive pulmonary disease (COPD). We aimed to assess the rate of decline in forced expiratory volume in 1 second (FEV1) in patients from a community cohort database in Korea. 5,865 subjects aged 40-69 years from the Ansung-Ansan cohort database I-III (2001-2006) were included in this study. We assessed the annual rate of decline in FEV1 over time in relation to smoking status, patient sex, and presence or absence of pre-bronchodilator airflow limitation using a generalized additive mixed model. The mean follow-up duration was 3.8 years. The annual mean decline in FEV1 in the entire cohort was significantly more rapid for men than women (31.3 mL vs 27.0 mL, P = 0.003). Among men without pre-bronchodilator airflow limitation, annual mean declines in FEV1 were 31.5, 35.5, and 40.1 mL for never smokers, former smokers (P = 0.09 vs. never smokers), and current smokers (P < 0.001 vs. never smokers), respectively; and 23.4, 19.7, and 33.9 mL, respectively, for men with pre-bronchodilator airflow limitation. Thus, among Korean males, smoking accelerates lung function decline over time whereas smoking cessation slows the rate of FEV1 decline regardless of pre-bronchodilator airflow limitation. This underscores the importance of smoking cessation in Koreans.ope