Risk Factors for Unfavorable Outcomes of Tuberculosis in Korea: Implications for Patient-Centered Care in Tuberculosis Treatment.

BACKGROUND: The treatment success rate for tuberculosis (TB) has stagnated at 80-81% in South Korea, indicating unsatisfactory outcomes. Enhancing treatment success rate necessitates the development of individualized treatment approaches for each patient. This study aimed to identify the risk factors associated with unfavorable treatment outcomes to facilitate tailored TB care. METHODS: We retrospectively analyzed the data of patients with active TB between January 2019 and December 2020 at a single tertiary referral center. We classified unfavorable treatment outcomes according to the 2021 World Health Organization guidelines as follows: "lost to follow-up" (LTFU), "not evaluated" (NE), "death," and "treatment failure" (TF). Moreover, we analyzed risk factors for each unfavorable outcome using Cox proportional hazard regression analysis. RESULTS: A total of 659 patients (median age 62 years; male 54.3%) were included in the study. The total unfavorable outcomes were 28.1%: 4.6% LTFU, 9.6% NE, 9.1% deaths, and 4.9% TF. Multivariate analysis showed that a culture-confirmed diagnosis of TB was associated with a lower risk of LTFU (adjusted hazard ratio [aHR], 0.25; 95% confidence interval [CI], 0.10-0.63), whereas the occurrence of adverse drug reactions (ADRs) significantly increased the risk of LTFU (aHR, 6.63; 95% CI, 2.63-16.69). Patients living far from the hospital (aHR, 4.47; 95% CI, 2.50-7.97) and those with chronic kidney disease (aHR, 3.21; 95% CI, 1.33-7.75) were at higher risk of being transferred out to other health institutions (NE). Higher mortality was associated with older age (aHR, 1.06; 95% CI, 1.04-1.09) and comorbidities. The ADRs that occurred during TB treatment were a risk factor for TF (aHR, 6.88; 95% CI, 2.24-21.13). CONCLUSION: Unfavorable outcomes of patients with TB were substantial at a tertiary referral center, and the risk factors for each unfavorable outcome varied. To improve treatment outcomes, close monitoring and the provision of tailored care for patients with TB are necessary.

Clinical Characteristics and Treatment Outcomes of Pulmonary Diseases Caused by Coinfections With Multiple Nontuberculous Mycobacterial Species.

BACKGROUND: Coinfections with multiple nontuberculous mycobacterial (NTM) species have not been widely studied. We aimed to evaluate the clinical characteristics and treatment outcomes in patients with NTM-pulmonary disease (PD) caused by coinfection with multiple NTM species. METHODS: We retrospectively reviewed patients with NTM-PD at a tertiary referral hospital in Korea between March 2012 and December 2018. Coinfection was defined as two or more species of NTM pathogens isolated from the same respiratory specimen or different specimens within three months. RESULTS: Among 1,009 patients with NTM-PD, 147 (14.6%) NTM coinfections were observed (average age 64.7 years, 69.4% women). NTM species were identified more frequently (median 6 vs. 3 times, P < 0.001) in the coinfection group than in the single species group, and follow-up duration was also longer in the coinfection group (median 44.9 vs. 27.1 months, P < 0.001). Mycobacterium avium complex (MAC) and M. abscessus and M. massiliense (MAB) were the dominant combinations (n = 71, 48.3%). For patients treated for over six months in the MAC plus MAB group (n = 31), sputum culture conversion and microbiological cure were achieved in 67.7% and 41.9% of patients, respectively. We divided the MAC plus MAB coinfection group into three subgroups according to the target mycobacteria; however, no statistical differences were found in the treatment outcomes. CONCLUSION: In NTM-PD cases, a significant number of multiple NTM species coinfections occurred. Proper identification of all cultured NTM species through follow-up is necessary to detect multispecies coinfections. Further research is needed to understand the nature of NTM-PD in such cases.

Association between exposure to specific PM2.5 constituents and environment, lifestyle, and clinical parameters in patients with COPD.

This study investigated the correlation between the individual chemical constituents of particulate matter 2.5 µm (PM2.5) and respiratory parameters as well as the living environment and daily behaviors in patients with chronic obstructive pulmonary disease (COPD). Data were obtained from prospective COPD panel conducted in South Korea. Following collection via a microPEM, 18 metallic elements were determined using energy-dispersive X-ray fluorescence spectroscopy. All participants completed detailed questionnaires on living environments and lifestyle practices. Eighty-nine stable COPD patients (mean age 68.1 years; 94.4% male) were analyzed. Several constituents (titanium, aluminum, bromine, and silicone) were significantly associated with respiratory outcomes. Copper and manganese concentrations were significantly associated with the living environment. Increased ventilation time and air purifier operation were associated with lower concentrations of copper, silicone, barium, and titanium. These findings suggest varying relationships between PM2.5 constituents and clinical parameters in COPD patients, providing a basis for personalized interventions and future research.

Longitudinal association between adiposity changes and lung function deterioration.

BACKGROUND: The longitudinal relationship between adiposity and lung function is controversial. We aimed to investigate the long-term association between adiposity changes and lung function in a middle-aged general Asian population. METHODS: In total, 5011 participants (average age, 54 years; 45% men) were enrolled from a community-based prospective cohort. During the follow-up period (median 8 years), both spirometry and bio-electrical impedance analysis were performed biannually. Individual slopes of the fat mass index (FMI; fat mass divided by the square of height in meters) and waist-to-hip ratio (WHR) were calculated using linear regression analysis. Multivariate linear mixed regression analysis was used to determine the long-term association between adiposity changes and lung function. RESULTS: The FMI was inversely associated with forced vital capacity (FVC) (estimated: - 31.8 mL in men, - 27.8 mL in women) and forced expiratory volume in 1 s (FEV1) (estimated: - 38.2 mL in men, - 17.8 mL in women) after adjusting for baseline age, height, residential area, smoking exposure (pack-years, men only), initial adiposity indices, and baseline lung function. The WHR was also inversely associated with FVC (estimated = - 1242.2 mL) and FEV1 (estimated = - 849.8 mL) in men. The WHR-increased group showed a more rapid decline in lung function than the WHR-decreased group in both the fat-gain and fat-loss groups. CONCLUSION: Adiposity was associated with the long-term impairment of lung function. Central obesity was the main driver of lung function impairment in the middle-aged general Asian population, regardless of fat mass changes.

Within-Host Evolution of SARS-CoV-2 in a B-Cell Depleted Patient With Successful Treatment.

Prolonged viral shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an immunocompromised host is a challenge as the treatment and infection control for chronic coronavirus disease 2019 infection is not well established and there is a potential risk of new variants emerging. A 48-year-old woman who underwent chemotherapy, including rituximab and steroid, had reactivation of SARS-CoV-2 68 days after the virus was first detected. She successfully recovered after receiving convalescent plasma and intravenous immunoglobulin. Genomic analysis demonstrated that viruses collected from the nasopharyngeal specimens at day 0 and day 68 had 18 different nucleotide mutations, implying within-host evolution after in-depth epidemiologic investigation.

Genomic characteristics of invasive mucinous adenocarcinoma of the lung with multiple pulmonary sites of involvement.

Invasive mucinous adenocarcinoma (IMA) of the lung frequently presents with diffuse pneumonic-type features or multifocal lesions, which are regarded as a pattern of intrapulmonary metastases. However, the genomics of multifocal IMAs have not been well studied. We performed whole exome sequencing on samples taken from 2 to 5 regions in seven patients with synchronous multifocal IMAs of the lung (24 regions total). Early initiating driver events, such as KRAS, NKX2-1, TP53, or ARID1A mutations, are clonal mutations and were present in all multifocal IMAs in each patient. The tumor mutational burden of multifocal IMAs was low (mean: 1.13/mega base), but further analyses suggested intra-tumor heterogeneity. The mutational signature analysis found that IMAs were predominantly associated with endogenous mutational process (signature 1), APOBEC activity (signatures 2 and 13), and defective DNA mismatch repair (signature 6), but not related to smoking signature. IMAs synchronously located in the bilateral lower lobes of two patients with background usual interstitial pneumonia had different mutation types, suggesting that they were double primaries. In conclusion, genomic evidence found in this study indicated the clonal intrapulmonary spread of diffuse pneumonic-type or multifocal IMAs, although they can occur in multicentric origins in the background of usual interstitial pneumonia. IMAs exhibited a heterogeneous genomic landscape despite the low somatic mutation burden. Further studies are warranted to determine the clinical significance of the genomic characteristics of IMAs in expanded cohorts.

Sarcopenia is associated with cardiovascular risk in men with COPD, independent of adiposity.

BACKGROUND: Sarcopenia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD), but its relationship with chronic obstructive pulmonary disease (COPD) has not been fully determined. This study is aimed to investigate the association between sarcopenia and risk for ASCVD in patients with COPD, independent of central obesity and fat mass. METHODS: Data regarding 704 men with COPD (mean age: 63.4 years) were extracted from the 2008 to 2011 Korean National Health and Nutrition Examination Surveys. Sarcopenia index and fat mass were assessed using dual-energy X-ray absorptiometry. Sarcopenia was defined according to the presence of sarcopenia index values < 1 standard deviation from the cutoff (0.774) among the study participants. ASCVD risk was evaluated using American College of Cardiology/American Heart Association guidelines. High probability of ASCVD was defined as ASCVD risk > 20%. RESULTS: The quartile-stratified sarcopenia index was negatively associated with ASCVD risk (P < 0.001). ASCVD risk and prevalence of high ASCVD risk were significantly greater in sarcopenic participants than in non-sarcopenic participants, regardless of central obesity and fat mass (all P < 0.001). Multivariate regression analyses demonstrated an independent association between sarcopenia and ASCVD risk (estimated ± standard error = 3.63 ± 0.77%, P < 0.001) and high ASCVD risk (odds ratio [OR] = 2.32, 95% confidence interval [CI] 1.05-5.15, P = 0.039). Furthermore, sarcopenia was an independent factor for high ASCVD risk in participants with moderate to very severe airflow limitation (OR = 2.97, 95% CI 1.06-8.36, P < 0.001). CONCLUSIONS: Sarcopenia was significantly associated with an increased risk for ASCVD in men with COPD, independent of central obesity and fat mass. High ASCVD risk was significantly associated with sarcopenia, particularly in participants with moderate to very severe airflow limitation.

Clinical impact of pneumothorax in patients with Pneumocystis jirovecii pneumonia and respiratory failure in an HIV-negative cohort.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) with acute respiratory failure can result in development of pneumothorax during treatment. This study aimed to identify the incidence and related factors of pneumothorax in patients with PCP and acute respiratory failure and to analyze their prognosis. METHODS: We retrospectively reviewed the occurrence of pneumothorax, including clinical characteristics and results of other examinations, in 119 non-human immunodeficiency virus patients with PCP and respiratory failure requiring mechanical ventilator treatment in a medical intensive care unit (ICU) at a tertiary-care center between July 2016 and April 2019. RESULTS: During follow up duration, twenty-two patients (18.5%) developed pneumothorax during ventilator treatment, with 45 (37.8%) eventually requiring a tracheostomy due to weaning failure. Cytomegalovirus co-infection (odds ratio 13.9; p = 0.013) was related with occurrence of pneumothorax in multivariate analysis. And development of pneumothorax was not associated with need for tracheostomy and mortality. Furthermore, analysis of survivor after 28 days in ICU, patients without pneumothorax were significantly more successful in weaning from mechanical ventilator than the patients with pneumothorax (44% vs. 13.3%, p = 0.037). PCP patients without pneumothorax showed successful home discharges compared to those who without pneumothorax (p = 0.010). CONCLUSIONS: The development of pneumothorax increased in PCP patient with cytomegalovirus co-infection, pneumothorax might have difficulty in and prolonged weaning from mechanical ventilators, which clinicians should be aware of when planning treatment for such patients.

The relationship between cognitive function and competence in inhaler technique in older adults with airway disease.

Cognitive impairment has high prevalence in older adults with airway diseases, and may influence their competence in inhaler use, thereby negatively affecting patient prognosis. We aimed to evaluate the relationship between cognitive function and competence in inhaler technique. We enrolled 108 inhaler naïve older adults (≥60 years) with airway disease in this prospective observational study and performed the Korean version of the Mini-Mental State Examination (K-MMSE). After explaining the inhaler technique, we scored its competence. While the total K-MMSE score was unrelated to the inhaler score, the orientation for place (estimates=0.62, p = 0.009), registration (estimates=0.988, p = 0.037), and recall (estimates=0.161, p = 0.048) were positively associated with the score. Low K-MMSE scores were associated with lower odds ratio for the competence of the "exhale" step (adjusted odds ratio= 0.23, p = 0.018). Thus, a K-MMSE-mediated evaluation of cognitive function in older adults with airway disease can be a useful tool to predict inhaler competence.

Relationship of the lung microbiome with PD-L1 expression and immunotherapy response in lung cancer.

BACKGROUND: Lung cancer is the primary cause of cancer-related deaths worldwide. The human lung serves as a niche to a unique and dynamic bacterial community that is related to the development of multiple diseases. Here, we investigated the differences in the lung microbiomes of patients with lung cancer. METHODS: 16S rRNA sequencing was performed to evaluate the respiratory tract microbiome present in the bronchoalveolar lavage fluid. Patients were stratified based on programmed death-ligand 1 (PD-L1) expression levels and immunotherapy responses. RESULTS: In total, 84 patients were prospectively analyzed, of which 59 showed low (< 10%), and 25 showed high (≥ 10%) PD-L1 expression levels. The alpha and beta diversities did not significantly differ between the two groups. Veillonella dispar was dominant in the high-PD-L1 group; the population of Neisseria was significantly higher in the low-PD-L1 group than in the high-PD-L1 group. In the immunotherapy responder group, V. dispar was dominant, while Haemophilus influenzae and Neisseria perflava were dominant in the non-responder group. CONCLUSION: The abundances of Neisseria and V. dispar differed significantly in relation to PD-L1 expression levels and immunotherapy responses.

Prevalence of depression and its associated factors in bronchiectasis: findings from KMBARC registry.

BACKGROUND: With the emergence of bronchiectasis as a common respiratory disease, epidemiological data have accumulated. However, the prevalence and impact of psychological comorbidities were not sufficiently evaluated. The present study examined the prevalence of depression and its associated factors in patients with bronchiectasis. METHODS: This study involved a multicenter cohort of bronchiectasis patients recruited from 33 pulmonary specialist hospitals. The baseline characteristics and bronchiectasis-related factors at enrollment were analyzed. Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). RESULTS: Of the 810 patients enrolled in the study, 168 (20.7%) patients had relevant depression (PHQ-9 score ≥ 10), and only 20 (11.9%) patients had a diagnosis of depression. Significant differences were noted in the depressive symptoms with disease severity, which was assessed using the Bronchiectasis Severity Index and E-FACED (all p < 0.001). Depressive symptoms inversely correlated with quality-of-life (r = - 0.704, p < 0.001) and positively correlated with fatigue severity score (r = 0.712, p < 0.001). Multivariate analysis showed that depression was significantly associated with the modified Medical Research Council dyspnea scale ≥ 2 (OR 2.960, 95% CI 1.907-4.588, p = < 0.001) and high number of exacerbations (≥ 3) in the previous year (OR 1.596, 95% CI 1.012-2.482, p = 0.041). CONCLUSIONS: Depression is common, but its association with bronchiectasis was underrecognized. It negatively affected quality-of-life and presented with fatigue symptoms. Among the bronchiectasis-related factors, dyspnea and exacerbation were closely associated with depression. Therefore, active screening for depression is necessary to optimize the treatment of bronchiectasis. TRIAL REGISTRATION: The study was registered at Clinical Research Information Service (CRiS), Republic of Korea (KCT0003088). The date of registration was June 19th, 2018.

Effectiveness of pirfenidone in idiopathic pulmonary fibrosis according to the autoantibody status: a retrospective cohort study.

BACKGROUND: Pirfenidone is an anti-fibrotic agent shown to slow the progression of idiopathic pulmonary fibrosis (IPF). However, its effectiveness in association with serological autoimmune features in IPF remains unclear. METHODS: We retrospectively reviewed the medical records of patients with IPF treated at a tertiary care hospital in South Korea. The autoantibody status was defined as positive if we detected autoantibodies meeting the serological domain criteria for interstitial pneumonia with autoimmune features or anti-neutrophil cytoplasmic antibodies. RESULTS: We included 142 patients with IPF treated with pirfenidone for over six months (93 were autoantibody-positive and 49 were autoantibody-negative). The mean age was 69.5 ± 7.3 years, and 77.5% of the patients were male. The adjusted mean changes over one year were - 34.4 and - 112.2 mL (p = 0.168) in forced vital capacity (FVC), and - 0.53 and - 0.72 mL/mmHg/min (p = 0.356) in the lungs diffusion capacity for carbon monoxide (DLCO) in the autoantibody-negative and autoantibody-positive groups, respectively. CONCLUSIONS: Reductions in FVC and DLCO were similar in autoantibody-positive and autoantibody-negative patients with IPF treated with pirfenidone. Pirfenidone is effective in attenuating the progression of IPF, irrespective of the autoantibody status.

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.

Thoracic skeletal muscle quantification: low muscle mass is related with worse prognosis in idiopathic pulmonary fibrosis patients.

BACKGROUND: Sarcopenia can contribute to negative outcomes in patients with various lung diseases. However, whether sarcopenia affects prognosis in patients with idiopathic pulmonary fibrosis (IPF) has not been reported. Simple measures of muscle mass, derived from chest computed tomography (CT), are increasingly being used to identify patients with sarcopenia. We hypothesized that skeletal muscle mass could be a predictor of prognosis in IPF patients. METHODS: We retrospectively evaluated 180 patients diagnosed with IPF between January 2010 and December 2015 at a tertiary care hospital in South Korea. We measured thoracic muscle volume by using the cross-sectional area (CSA) of the pectoralis, paraspinal, serratus, and latissimus muscles at the 4th vertebral region (T4CSA) and the erector spinae muscle (ESMCSA) at the 12th vertebral region. CT scans at the time of diagnosis were used for analysis and respective CSA were divided by height squared to normalize for stature. Survival times were estimated with the Kaplan-Meier method and compared with the log-rank test. Multivariate Cox proportional hazards models were performed to investigate relationships between clinical parameters and mortality. RESULTS: Male patients in the lowest quartile of T4CSA divided by height squared (m2) (T4MI) and in the lowest quartile of ESMCSA divided by height squared (m2) (T12MI) were more likely to have higher Gender-Age-Physiology Index scores (T4MI, 3.3 ± 1.3 vs 4.0 ± 1.6, P = 0.012; T12MI, 3.2 ± 1.3 vs 4.1 ± 1.6, P = 0.002). Male patients in the lowest quartile of T4MI exhibited a significantly lower survival rate (P = 0.035). After multivariate Cox proportional hazards analysis, T4MI was a significant risk factor for all-cause mortality (HR, 0.955; 95% CI, 0.913-0.998; P = 0.041), whereas T12MI was not (HR, 0.980; 95% CI, 0.856-1.121; P = 0.766). CONCLUSIONS: Low skeletal mass normalized for stature at the level of 4th vertebrae which can be acquired by quantifying thoracic skeletal muscle on single-slice axial chest CT, may be a strong risk factor for all-cause mortality in patients with IPF. TRIAL REGISTRATION: The research protocol was approved by the Institutional Review Board of Severance Hospital, South Korea (IRB No.4-2018-0454).

Prognostic impact of the ratio of the main pulmonary artery to that of the aorta on chest computed tomography in patients with idiopathic pulmonary fibrosis.

BACKGROUND: In many clinical disorders, there is a relationship between the ratio of the diameter of the main pulmonary artery (mPA) to that of the aorta (Ao) on chest computed tomography (CT). The aim of this study was to determine if the mPA/Ao ratio at diagnosis is associated with the clinical characteristics and outcomes in patients with idiopathic pulmonary fibrosis (IPF). METHODS: We retrospectively reviewed the diameters of the pulmonary artery and aorta on chest CT, clinical characteristics, and results of other examinations in 303 patients at the time of initial diagnosis of IPF at our tertiary care center between 2011 and 2015. The primary outcomes were death and lung transplantation. The patients were followed up until June 2017. RESULTS: One hundred and eight patients (35.6%) died and 58 (19.1%) underwent lung transplantation during follow-up. The mean mPA and Ao diameters were 28.3 mm and 34.0 mm, respectively, and the mean mPA/Ao ratio was 0.84. Thirty-one patients (10.2%) had an mPA/Ao ratio > 1.0 and 182 (60.1%) had an mPA/Ao ratio > 0.8. Patients with an mPA/Ao ratio > 0.8 had a lower DLco value than those with an mPA/Ao ratio ≤ 0.8. In Kaplan-Meier analysis, patients with an mPA/Ao ratio > 1.0 or > 0.8 had worse outcomes than those with an mPA/Ao ratio ≤ 1.0 and ≤ 0.8, respectively. CONCLUSIONS: A higher mPA/Ao ratio based on 1.0 and 0.8 is associated with unfavorable prognosis in patients with IPF.

Erythropoietin-Producing Hepatoma Receptor Tyrosine Kinase A2 Modulation Associates with Protective Effect of Prone Position in Ventilator-induced Lung Injury.

The erythropoietin-producing hepatoma (Eph) receptor tyrosine kinase A2 (EphA2) and its ligand, ephrinA1, play a pivotal role in inflammation and tissue injury by modulating the epithelial and endothelial barrier integrity. Therefore, EphA2 receptor may be a potential therapeutic target for modulating ventilator-induced lung injury (VILI). To support this hypothesis, here, we analyzed EphA2/ephrinA1 signaling in the process of VILI and determined the role of EphA2/ephrinA1 signaling in the protective mechanism of prone positioning in a VILI model. Wild-type mice were ventilated with high (24 ml/kg; positive end-expiratory pressure, 0 cm; 5 h) tidal volume in a supine or prone position. Anti-EphA2 receptor antibody or IgG was administered to the supine position group. Injury was assessed by analyzing the BAL fluid, lung injury scoring, and transmission electron microscopy. Lung lysates were evaluated using cytokine/chemokine ELISA and Western blotting of EphA2, ephrinA1, PI3Kγ, Akt, NF-κB, and P70S6 kinase. EphA2/ephrinA1 expression was higher in the supine high tidal volume group than in the control group, but it did not increase upon prone positioning or anti-EphA2 receptor antibody treatment. EphA2 antagonism reduced the extent of VILI and downregulated the expression of PI3Kγ, Akt, NF-κB, and P70S6 kinase. These findings demonstrate that EphA2/ephrinA1 signaling is involved in the molecular mechanism of VILI and that modulation of EphA2/ehprinA1 signaling by prone position or EphA2 antagonism may be associated with the lung-protective effect. Our data provide evidence for EphA2/ehprinA1 as a promising therapeutic target for modulating VILI.

Association of serum bilirubin level with lung function decline: a Korean community-based cohort study.

BACKGROUND: Bilirubin has been reported to be associated with respiratory diseases due to its antioxidant action. We aimed to evaluate the relationship between serum bilirubin concentration and annual lung function decline in the Korean general population. METHODS: The study included 7986 subjects aged 40-69 years from the Ansung-Ansan cohort database I (2001-2002)-III (2005-2006). We analyzed the relationships between serum bilirubin level and forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and mean forced expiratory flow between 25 and 75% of FVC (FEF25-75%) at baseline, as well as the annual average changes in these lung parameters. RESULTS: The FEV1, FVC, and FEF25-75% were significantly associated with serum bilirubin levels after adjustment for age, sex, body mass index (BMI), and smoking status (all P < 0.001). When stratified according to smoking status, these relationships were significant in never-smokers. Additionally, serum bilirubin level was negatively associated with the annual decline in FEV1 and FVC, and positively associated with the annual decline in FEV1/FVC after adjustment for age, sex, BMI, baseline lung function, and smoking status (all P < 0.001). CONCLUSIONS: We found significant associations of serum bilirubin levels with FEV1, FVC, and FEF25-75% in the general population, especially in never-smokers. Moreover, serum bilirubin levels were related with the annual decline in FEV1, FVC, and FEV1/FVC ratio.

All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling.

The role of all-trans retinoic acid (ATRA) in pulmonary fibrosis is relatively unknown, although this metabolite modulates cell differentiation, proliferation, and development. We aimed to evaluate the role of ATRA in bleomycin-induced pulmonary fibrosis, and whether the mechanism involves EphA2-EphrinA1 and PI3K-Akt signaling. We evaluated three groups of mice: a control group (intraperitoneal DMSO injection 3 times weekly after PBS instillation), bleomycin group (intraperitoneal DMSO injection 3 times weekly after bleomycin instillation), and bleomycin + ATRA group (intraperitoneal ATRA injection 3 times weekly after bleomycin instillation). The cell counts and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology, Ashcroft score, hydroxyproline assay, expression of several signal pathway proteins including EphA2-EphrinA1, and PI3K-Akt, and cytokine levels were compared among the groups. We found that bleomycin significantly increased the protein concentration in the BALF, Ashcroft score in lung tissue, and hydroxyproline contents in lung lysates. Furthermore, bleomycin upregulated EphA2, EphrinA1, PI3K 110γ, Akt, IL-6 and TNF-α. However, administration of ATRA attenuated the upregulation of EphA2-EphrinA1 and PI3K-Akt after bleomycin instillation, and decreased pulmonary fibrosis. In addition, ATRA suppressed IL-6 and TNF-α production induced by bleomycin-induced injury. Collectively, these data suggest that ATRA attenuates bleomycin-induced pulmonary fibrosis by regulating EphA2-EphrinA1 and PI3K-Akt signaling.

Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer.

BACKGROUND: Methionyl-tRNA synthetase (MRS) plays a critical role in initiating translation by transferring Met to the initiator tRNA (tRNAiMet) and protection against ROS-mediated damage, suggesting that its overexpression is related to cancer growth and drug resistance. In this study, the clinical implication of MRS expression in non-small cell lung cancer (NSCLC) was evaluated. METHODS: Immunoblot and immunohistochemical (IHC) analyses were performed using tissue lysates and formalin-fixed paraffin embedded (FFPE) tissue blocks from wild type C57BL/6, LSL-Kras G12D, and LSL-Kras G12D:p53fl/fl mice. For human studies, 12 paired adjacent normal appearing lung tissue lysates and cancer tissue lysates, in addition to 231 FFPE tissue samples, were used. RESULTS: MRS was weakly expressed in the spleen and intestinal epithelium and only marginally expressed in the kidney, liver, and lungs of wild type C57BL/6 mice. On the other hand, MRS was strongly expressed in the neoplastic region of lung tissue from LSL-Kras G12D and LSL-Kras G12D:p53fl/fl mice. Immunoblot analysis of the human normal appearing adjacent and lung cancer paired tissue lysates revealed cancer-specific MRS overexpression, which was related to mTORC1 activity. IHC analysis of the 231 FFPE lung cancer tissue samples showed that MRS expression was frequently detected in the cytoplasm of lung cancer cells (179 out of 231, 77.4%), with a small proportion (73 out of 231, 31.6%) also showing nuclear expression. The proportion of cases with positive MRS expression was higher in the advanced pStage subgroup (P = 0.018, χ2-test) and cases with MRS expression also had shorter DFS (161.6 vs 142.3, P = 0.014, log-rank test). CONCLUSIONS: Taken together, MRS is frequently overexpressed in NSCLC. Moreover, MRS is related to mTORC1 activity and its overexpression is associated with poor clinical outcomes, indicating that it has potential as a putative therapeutic target.