Prior pneumococcal vaccination improves in-hospital mortality among elderly population hospitalized due to community-acquired pneumonia.

BACKGROUND: Pneumococcal vaccination is a preventive method to reduce pneumonia related mortality. However, real-world data on efficacy of the pneumococcal vaccine in reducing mortality is lacking, especially in elderly patients. This study was conducted to assess the effects of prior pneumococcal vaccination in elderly pneumonia patients. METHODS: The data was procured from the Health Insurance Review and Assessment and Quality Assessment database. Hospitalized patients who met the criteria of community-acquired pneumonia (CAP) were included and they were grouped according to vaccination state. Patients were aged ≥ 65 years and treated with beta-lactam, quinolone, or macrolide. Patients were excluded when treatment outcomes were unknown. RESULTS: A total of 4515 patients were evaluated, and 1609 (35.6%) of them were vaccinated prior to hospitalization. Mean age was 77.0 [71.0;82.0], 54.2% of them were male, and mean Charlson comorbidity index (CCI) was 3.0. The patients in the vaccinated group were younger than those in the unvaccinated group (76.0 vs. 78.0 years; P < 0.001), and showed higher in-hospital improvement (97.6 vs. 95.0%; P < 0.001) and lower 30-day mortality (2.6 vs. 5.3%; P < 0.001). After adjusting confounding factors such as age, gender, CURB score and CCI score, the vaccinated group demonstrated a significant reduction in 30-day mortality (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.41-0.81; P < 0.01) and in-hospital mortality (HR 0.53, 95% CI0.37-0.78; P < 0.001) compared to the unvaccinated group in multivariate analysis. Vaccinated group showed better 30-day survival than those in non-vaccinated group (log-rank test < 0.05). CONCLUSIONS: Among elderly hospitalized CAP patients, prior pneumococcal vaccination was associated with improved in-hospital mortality and 30-day mortality.

Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF-ß1 activity.

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level >75.659 ng/mL than in the group with an OAT level ≤75.659 ng/mL (HR, 29.53; p = 0.0008). OAT overexpression and knockdown increased and decreased ECM component production by lung fibroblasts, respectively. OAT knockdown also inhibited transforming growth factor-ß1 (TGF)-ß1 activity and TGF-ß1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, increased OAT levels in lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-ß1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

Overexpression of fatty acid synthase attenuates bleomycin induced lung fibrosis by restoring mitochondrial dysfunction in mice.

Proper lipid metabolism is crucial to maintain alveolar epithelial cell (AEC) function, and excessive AEC death plays a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The mRNA expression of fatty acid synthase (FASN), a key enzyme in the production of palmitate and other fatty acids, is downregulated in the lungs of IPF patients. However, the precise role of FASN in IPF and its mechanism of action remain unclear. In this study, we showed that FASN expression is significantly reduced in the lungs of IPF patients and bleomycin (BLM)-treated mice. Overexpression of FASN significantly inhibited BLM-induced AEC death, which was significantly potentiated by FASN knockdown. Moreover, FASN overexpression reduced BLM-induced loss of mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). Oleic acid, a fatty acid component increased by FASN overexpression, inhibited BLM-induced cell death in primary murine AECs and rescue BLM induced mouse lung injury/fibrosis. FASN transgenic mice exposed to BLM exhibited attenuated lung inflammation and collagen deposition compared to controls. Our findings suggest that defects in FASN production may be associated with the pathogenesis of IPF, especially mitochondrial dysfunction, and augmentation of FASN in the lung may have therapeutic potential in preventing lung fibrosis.

COVID-19 Vaccine-Associated Pneumonitis in the Republic of Korea: A Nationwide Multicenter Survey.

BACKGROUND: Recent reports have suggested that pneumonitis is a rare complication following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, its clinical features and outcomes are not well known. The aim of this study was to identify the clinical characteristics and outcomes of patients with vaccine-associated pneumonitis following vaccination against SARS-CoV-2. METHODS: In this nationwide multicenter survey study, questionnaires were distributed to pulmonary physicians in referral hospitals. They were asked to report cases of development or exacerbation of interstitial lung disease (ILD) associated with the coronavirus disease 2019 vaccine. Vaccine-associated pneumonitis was defined as new pulmonary infiltrates documented on chest computed tomography within 4 weeks of vaccination and exclusion of other possible etiologies. RESULTS: From the survey, 49 cases of vaccine-associated pneumonitis were identified between February 27 and October 30, 2021. After multidisciplinary discussion, 46 cases were analyzed. The median age was 66 years and 28 (61%) were male. The median interval between vaccination and respiratory symptoms was 5 days. There were 20 (43%), 17 (37%), and nine (19%) patients with newly identified pneumonitis, exacerbation of pre-diagnosed ILD, and undetermined pre-existing ILD, respectively. The administered vaccines were BNT162b2 and ChAdOx1 nCov-19/AZD1222 each in 21 patients followed by mRNA-1273 in three, and Ad26.COV2.S in one patient. Except for five patients with mild disease, 41 (89%) patients were treated with corticosteroid. Significant improvement was observed in 26 (57%) patients including four patients who did not receive treatment. However, ILD aggravated in 9 (20%) patients despite treatment. Mortality was observed in eight (17%) patients. CONCLUSION: These results suggest pneumonitis as a potentially significant safety concern for vaccines against SARS-CoV-2. Clinical awareness and patient education are necessary for early recognition and prompt management. Additional research is warranted to identify the epidemiology and characterize the pathophysiology of vaccine-associated pneumonitis.

New prognostic scoring system for mortality in idiopathic pulmonary fibrosis by modifying the gender, age, and physiology model with desaturation during the six-minute walk test.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD) with variable and heterogeneous clinical course. The GAP (gender, age, and physiology) model had been used to predict mortality in patients with IPF, but does not contain exercise capacity. Therefore, our aim in this study was to develop new prognostic scoring system in the Korea IPF Cohort (KICO) registry. Materials and methods: This is a retrospective study of Korean patients with IPF in KICO registry from June 2016 to August 2021. We developed new scoring system (the GAP6) based on the GAP model adding nadir saturation of percutaneous oxygen (SpO2) during six-minute walk test (6MWT) in the KICO registry and compared the efficacy of the GAP and the GAP6 model. Results: Among 2,412 patients in KICO registry, 966 patients were enrolled. The GAP6 model showed significant prognostic value for mortality between each stage [HR Stage II vs. Stage I = 2.89 (95% CI = 2.38-3.51), HR Stage III vs. Stage II = 2.68 (95% CI = 1.60-4.51)]. In comparison the model performance with area under curve (AUC) using receiver operating characteristic (ROC) curve analysis, the GAP6 model showed a significant improvement for predicting mortality than the GAP model (AUC the GAP vs. the GAP6, 0.646 vs. 0.671, p < 0.0019). Also, the C-index values slightly improved from 0.674 to 0.691 for mortality. Conclusion: The GAP6 model adding nadir SpO2 during 6WMT for an indicator of functional capacity improves prediction ability with C-index and AUC. Additional multinational study is needed to confirm these finding and validate the applicability and accuracy of this risk assessment system.

Continuing Quality Assessment Program Improves Clinical Outcomes of Hospitalized Community-Acquired Pneumonia: A Nationwide Cross-Sectional Study in Korea.

BACKGROUND: Pneumonia, which is the third leading cause of death in South Korea, is continuously increasing with the aging society. The Health Insurance Review and Assessment of South Korea conducted a quality assessment (QA) for improving the outcome of community-acquired pneumonia (CAP). METHODS: We conducted a nationwide cross-sectional study of hospitalized CAP in South Korea. First to third QA data were gathered into a single database. The national health insurance database was merged with the QA database for analyzing the medical claims data. Comorbidities, pneumonia severity, and pneumonia care appropriateness were calculated using Charlson comorbidity index (CCI), CURB-65, and core assessment of CAP scores (CAP scores), respectively. RESULTS: Overall, 54,307 patients were enrolled. The CAP scores significantly improved on QA program implementation (P < 0.001). All the variables demonstrated an association with in-hospital mortality, hospital length of stay (LOS), and 30-day mortality in the univariate analyses. Following the adjustments, higher CCI and CURB-65 scores were associated with higher in-hospital mortality, longer hospital LOS, and higher 30-day mortality. Male sex was associated with higher in-hospital/30-day mortality and shorter hospital LOS. Higher CAP scores were associated with shorter hospital LOS (P < 0.001). Upon QA program implementation, in-hospital mortality (P < 0.001), hospital LOS (P < 0.001), and 30-day mortality (P < 0.001) improved. CONCLUSION: Continuing QA program is effective in improving the clinical outcomes of hospitalized CAP.

miRNA-6515-5p regulates particulate matter-induced inflammatory responses by targeting CSF3 in human bronchial epithelial cells.

Particulate matter (PM) is associated with the incidence, exacerbation, and mortality of variable respiratory diseases. However, the molecular mechanisms of PM10-mediated inflammation are unclear. We identified microRNAs (miRNAs) and messenger RNAs (mRNAs) related to the inflammatory response in PM10-exposed bronchial epithelial cells using next-generation sequencing. Of the miRNAs, miR-6515-5p was significantly downregulated in PM10-exposed human bronchial epithelial BEAS-2B cells. miR-6515-5p regulated the production of pro-inflammatory cytokines (IL-6 and IL-8) and the expression of inflammatory genes (IL-1ß, IL-6, IL-8, TNF-α, CXCL-1, and MCP-1) via MAPK/ERK signaling; overexpression of miR-6515-5p using a mimic inhibited PM10-induced inflammatory responses via inactivation of the ERK pathway, whereas downregulation of miR-6515-5p via an inhibitor significantly increased inflammation in PM10-exposed cells via activation of ERK. Furthermore, we identified colony stimulating factor 3 (CSF3) as a target gene of miR-6515-5p using TargetScanHuman, and confirmed the association between miR-6515-5p and CSF3 using a luciferase reporter assay. Furthermore, we found that mRNA and protein levels of CSF3 were negatively regulated by miR-6515-5p. Inhibition of CSF3 by small interfering RNA significantly reduced the expression and production of inflammatory markers in PM10-exposed cells by inactivating the MAPK/ERK signaling pathway. Therefore, we suggest that miR-6515-5p regulates PM10-induced inflammatory responses by targeting CSF3 via MAPK/ERK signaling in bronchial epithelial cells.

Histone deacetylase 3 promotes alveolar epithelial-mesenchymal transition and fibroblast migration under hypoxic conditions.

Epithelial-mesenchymal transition (EMT), a process by which epithelial cells undergo a phenotypic conversion that leads to myofibroblast formation, plays a crucial role in the progression of idiopathic pulmonary fibrosis (IPF). Recently, it was revealed that hypoxia promotes alveolar EMT and that histone deacetylases (HDACs) are abnormally overexpressed in the lung tissues of IPF patients. In this study, we showed that HDAC3 regulated alveolar EMT markers via the AKT pathway during hypoxia and that inhibition of HDAC3 expression by small interfering RNA (siRNA) decreased the migration ability and invasiveness of diseased human lung fibroblasts. Furthermore, we found that HDAC3 enhanced the migratory and invasive properties of fibroblasts by positively affecting the EMT process, which in turn was affected by the increased and decreased levels of microRNA (miR)-224 and Forkhead Box A1 (FOXA1), respectively. Lastly, we found this mechanism to be valid in an in vivo system; HDAC3 siRNA administration inhibited bleomycin-induced pulmonary fibrosis in mice. Thus, it is reasonable to suggest that HDAC3 may accelerate pulmonary fibrosis progression under hypoxic conditions by enhancing EMT in alveolar cells through the regulation of miR-224 and FOXA1. This entire process, we believe, offers a novel therapeutic approach for pulmonary fibrosis.

Overexpression of V-ATPase B2 attenuates lung injury/fibrosis by stabilizing lysosomal membrane permeabilization and increasing collagen degradation.

Excessive oxidative stress causes lysosomal membrane permeabilization (LMP), which leads to cell death. Vacuolar ATPase (V-ATPase) is the enzyme responsible for pumping H+ into the cytosol and thus maintaining intracellular pH. Previously, we reported that V-ATPase B2 subunit expression is upregulated in the TiO2-exposed lung epithelium. We investigated the role of the lysosomal V-ATPase B2 subunit in oxidative stress-induced alveolar epithelial cell death and in an experimental lung injury/fibrosis model. Overexpression of V-ATPase B2 increased lysosomal pH and lysosomal activities in the cells. In the presence of H2O2, overexpression of V-ATPase B2 increased survival, and silencing of V-ATPase B2 dramatically increased cell death. Overexpression of V-ATPase B2 diminished H2O2-triggered LMP, as evidenced by a reduction in acridine orange staining and leakage of cathepsin D from the lysosome to the cytoplasm. In addition, V-ATPase B2-overexpressing macrophages exhibited significantly enhanced uptake and degradation of collagen. V-ATPase B2-overexpressing transgenic mice showed significant inhibition of the bleomycin-induced increases in lung inflammation and fibrosis. We conclude that V-ATPase B2 is critical for maintaining lysosomal activities against excessive oxidative stress by stabilizing LMP. Our findings reveal a previously unknown role of this V-ATPase subunit in a lung injury and fibrosis model.

Clinical Features, Diagnosis, Management, and Outcomes of Idiopathic Pulmonary Fibrosis in Korea: Analysis of the Korea IPF Cohort (KICO) Registry.

BACKGROUND: The Korea Interstitial Lung Disease Study Group has made a new nationwide idiopathic pulmonary fibrosis (IPF) registry because the routine clinical practice has changed due to new guidelines and newly developed antifibrotic agents in the recent decade. The aim of this study was to describe recent clinical characteristics of Korean IPF patients. METHODS: Both newly diagnosed and following IPF patients diagnosed after the previous registry in 2008 were enrolled. Survival analysis was only conducted for patients diagnosed with IPF after 2016 because antifibrotic agents started to be covered by medical insurance of Korea in October 2015. RESULTS: A total of 2,139 patients were analyzed. Their mean age at diagnosis was 67.4±9.3 years. Of these patients, 76.1% were males, 71.0% were ever-smokers, 14.4% were asymptomatic at the time of diagnosis, and 56.9% were at gender-agephysiology stage I. Occupational toxic material exposure was reported in 534 patients. The mean forced vital capacity was 74.6% and the diffusing capacity for carbon monoxide was 63.6%. Treatment with pirfenidone was increased over time: 62.4% of IPF patients were treated with pirfenidone initially. And 79.2% of patients were treated with antifiboritics for more than three months during the course of the disease since 2016. Old age, acute exacerbation, treatment without antifibrotics, and exposure to wood and stone dust were associated with higher mortality. CONCLUSION: In the recent Korean IPF registry, the percentage of IPF patients treated with antifibrotics was increased compared to that in the previous IPF registry. Old age, acute exacerbation, treatment without antifibrotics, and exposure to wood and stone dust were associated with higher mortality.

Long-Term Prognosis of Asthma-Bronchiectasis Overlapped Patients: A Nationwide Population-Based Cohort Study.

PURPOSE: Asthma and bronchiectasis are common chronic respiratory diseases, and their coexistence is frequently observed but not well investigated. Our aim was to study the effect of comorbid bronchiectasis on asthma. METHODS: A propensity score-matched cohort study was conducted using the National Health Insurance Service-Health Screening Cohort database. From 2005 to 2008, 8,034 participants with asthma were weighted based on propensity scores in a 1:3 ratio with 24,099 participants without asthma. From the asthma group, 141 participants with overlapped bronchiectasis were identified, and 7,892 participants had only asthma. Clinical outcomes of acute asthma exacerbation(s) and mortality rates were compared among the study groups. RESULTS: The prevalence of bronchiectasis (1.7%) was 3 times higher in asthmatics than in the general population of Korea. Patients who had asthma comorbid with bronchiectasis experienced acute exacerbation(s) more frequently than non-comorbid patients (11.3% vs. 5.8%, P = 0.007). Time to the first acute exacerbation was also shorter in the asthmatics with bronchiectasis group (1,970.9 days vs. 2,479.7 days, P = 0.005). Although bronchiectasis was identified as a risk factor for acute exacerbation (adjusted odds ratio, 1.73; 95% confidence interval [CI], 1.05-2.86), there was no significant relationship between bronchiectasis and all-cause or respiratory mortality (adjusted hazard ratio [aHR], 1.17; 95% CI, 0.67-2.04 and aHR, 0.81; 95% CI, 0.11-6.08). CONCLUSIONS: Comorbid bronchiectasis increases asthma-related acute exacerbation, but it does not-raise the risk of all-cause or respiratory mortality. Close monitoring and accurate diagnosis of bronchiectasis are required for patients with frequent exacerbations of asthma.

A Soft Voting Ensemble-Based Model for the Early Prediction of Idiopathic Pulmonary Fibrosis (IPF) Disease Severity in Lungs Disease Patients.

Idiopathic pulmonary fibrosis, which is one of the lung diseases, is quite rare but fatal in nature. The disease is progressive, and detection of severity takes a long time as well as being quite tedious. With the advent of intelligent machine learning techniques, and also the effectiveness of these techniques, it was possible to detect many lung diseases. So, in this paper, we have proposed a model that could be able to detect the severity of IPF at the early stage so that fatal situations can be controlled. For the development of this model, we used the IPF dataset of the Korean interstitial lung disease cohort data. First, we preprocessed the data while applying different preprocessing techniques and selected 26 highly relevant features from a total of 502 features for 2424 subjects. Second, we split the data into 80% training and 20% testing sets and applied oversampling on the training dataset. Third, we trained three state-of-the-art machine learning models and combined the results to develop a new soft voting ensemble-based model for the prediction of severity of IPF disease in patients with this chronic lung disease. Hyperparameter tuning was also performed to get the optimal performance of the model. Fourth, the performance of the proposed model was evaluated by calculating the accuracy, AUC, confusion matrix, precision, recall, and F1-score. Lastly, our proposed soft voting ensemble-based model achieved the accuracy of 0.7100, precision 0.6400, recall 0.7100, and F1-scores 0.6600. This proposed model will help the doctors, IPF patients, and physicians to diagnose the severity of the IPF disease in its early stages and assist them to take proactive measures to overcome this disease by enabling the doctors to take necessary decisions pertaining to the treatment of IPF disease.

Humidifier Disinfectant Consumption and Humidifier Disinfectant-Associated Lung Injury in South Korea: A Nationwide Population-Based Study.

Humidifier disinfectant (HD) is a household biocidal product used in humidifier water tanks to prevent the growth of microorganisms. In 2011, a series of lung injury cases of unknown causes emerged in children and pregnant women who had used HD in Korea. This study investigated changes in the nationwide number of cases of humidifier disinfectant-associated lung injury (HDLI) in concordance with nationwide HD consumption using data covering the entire Korean population. More than 25 kinds of HD products were sold between 1994 and 2011. The number of diagnosed HDLI, assessed by S27.3 (other injuries of lungs) of the Korea National Health Insurance Service (NHIS) data, sharply increased by 2005, subsequently decreased after 2005, and almost disappeared after 2011 in concordance with the annual number of HD sales. The number of self-reported HDLIs, assessed using data from all suspected HDLI cases registered in the Korea Ministry of Environment, changed with the annual number of HD sales, with a delay pattern, potentially induced by the late awareness of lung injury diseases. The present study suggests that changes in the nationwide annual consumption of HD products were consistent with changes in the annual number of HDLI cases in Korea.

Comparison of Pharmacokinetics and Anti-Pulmonary Fibrosis-Related Effects of Sulforaphane and Sulforaphane N-acetylcysteine.

Sulforaphane (SFN), belonging to the isothiocyanate family, has received attention owing to its beneficial activities, including chemopreventive and antifibrotic effects. As sulforaphane N-acetylcysteine (SFN-NAC), a major sulforaphane metabolite, has presented similar pharmacological activities to those of SFN, it is crucial to simultaneously analyze the pharmacokinetics and activities of SFN and SFN-NAC, to comprehensively elucidate the efficacy of SFN-containing products. Accordingly, the anti-pulmonary fibrotic effects of SFN and SFN-NAC were assessed, with simultaneous evaluation of permeability, metabolic stability, and in vivo pharmacokinetics. Both SFN and SFN-NAC decreased the levels of transforming growth factor-ß1-induced fibronectin, alpha-smooth muscle actin, and collagen, which are major mediators of fibrosis, in MRC-5 fibroblast cells. Regarding pharmacokinetics, SFN and SFN-NAC were metabolically unstable, especially in the plasma. SFN-NAC degraded considerably faster than SFN in plasma, with SFN being formed from SFN-NAC. In rats, SFN and SFN-NAC showed a similar clearance when administered intravenously; however, SFN showed markedly superior absorption when administered orally. Although the plasma SFN-NAC concentration was low owing to poor absorption following oral administration, SFN-NAC was converted to SFN in vivo, as in plasma. Collectively, these data suggest that SFN-NAC could benefit a prodrug formulation strategy, possibly avoiding the gastrointestinal side effects of SFN, and with improved SFN-NAC absorption.

Longitudinal Changes in Clinical Features, Management, and Outcomes of Idiopathic Pulmonary Fibrosis. A Nationwide Cohort Study.

Rationale: In recent decades, diagnosis and treatment recommendations for idiopathic pulmonary fibrosis (IPF) have changed. In Korea, the average life expectancy has increased, unmet healthcare needs have been reduced, and the number of computed tomographic examinations performed has nearly doubled. The Korean Interstitial Lung Disease Study Group conducted a nationwide cohort study for idiopathic interstitial pneumonia, including IPF, and established a registry for IPF.Objectives: Using study data collected by the study group, this study aimed to evaluate longitudinal changes in clinical features, diagnosis, treatment, and mortality and analyze the extent to which changes in medication usage affected IPF-associated mortality.Methods: The study population included newly diagnosed patients with IPF from a cohort study (January 2002 to September 2008, n = 1,839, 2008 group) and prospective registry (January 2012 to August 2018, n = 1,345, 2018 group). Survival curves were estimated using the Kaplan-Meier method, and Cox regression models were used to identify mortality-associated risk factors in each group.Results: The 2018 group was younger, had fewer symptoms, had less honeycombing, underwent more serologic autoimmune marker and pulmonary function tests, had higher oxygen partial pressure and lower carbon dioxide partial pressure values, was less frequently diagnosed by surgical biopsy, and had better survival than the 2008 group. Steroid use and conservative care declined, whereas N-acetylcysteine use increased in this group. Antifibrotic agents were used in only the 2018 group. In the 2008 group, N-acetylcysteine was associated with lower mortality, whereas conservative care was associated with higher mortality. In the 2018 group, the use of antifibrotic agents was associated with lower mortality, and steroid use was associated with higher mortality. The survival rates in the 2008 and 2018 non-antifibrotic agent subgroups were similar.Conclusions: This study analyzed national IPF cohort data spanning 17 years. In clinical practice, the IPF diagnosis was made earlier, steroid and immunosuppressive agent use was reduced, and antifibrotic agents were administered. The survival of patients with IPF has improved over the decades, and antifibrotic use was consistently associated with improved survival.Clinical trial registered with clinicaltrials.gov (NCT04160715).

Anti­inflammatory activity of 3,5,6,7,3',4'­hexamethoxyflavone via repression of the NF­κB and MAPK signaling pathways in LPS­stimulated RAW264.7 cells.

Citrus peel has been used as a Traditional medicine in Asia to treat coughs, asthma and bronchial disorders. Therefore, the anti­inflammatory effects of 3,5,6,7,3',4'­hexamethoxyflavone (quercetogetin, QUE) isolated from Citrus unshiu peel were investigated in lipopolysaccharide (LPS)­induced RAW 264.7 macrophage cells. The results showed that QUE repressed the production of prostaglandin E2 and nitric oxide by suppressing LPS­induced expression of cyclooxygenase­2 and inducible nitric oxide synthase. It also suppressed the production of interleukin (IL)­6, IL­1ß, and tumor necrosis factor­α cytokines, and decreased the nuclear translocation of NF­κB by interrupting the phosphorylation of NF­κB inhibitor α in macrophage cells. Based on the finding that QUE inhibited the phosphorylation of ERK protein expression in LPS­induced RAW264.7 cells, it was confirmed that inhibition of inflammatory responses by QUE was mediated via the ERK pathway. Therefore, this study suggests that QUE has strong anti­inflammatory effects, making it a promising compound for use as a therapeutic agent in treating inflammatory lung diseases, such as emphysema.

Effects of antioxidants on oxidative stress and inflammatory responses of human bronchial epithelial cells exposed to particulate matter and cigarette smoke extract.

Particulate matter (PM) is a type of air pollutant that induces adverse health effects, including acute exacerbation of chronic obstructive pulmonary disease (COPD). However, the effects of co-exposure to PM and cigarette smoke extract (CSE) on bronchial epithelial cells remain unknown. This study investigated the cytotoxic and pro-inflammatory effects of combined exposure to PM and CSE on bronchial epithelial cells, and assessed the potential of antioxidants to inhibit CSE/PM-induced oxidative stress and inflammation. Exposure of epithelial cells to PM or CSE induced cytotoxicity, inflammation, and oxidative stress, all of which were dramatically increased when cells were exposed to the combination of CSE and PM. Importantly, the adverse effects of CSE/PM exposure were suppressed when cells were treated with sulforaphane (SFN) or sulforaphane N-acetylcysteine (SFNAC). Furthermore, SFN and SFNAC suppressed the CSE/PM-induced pro-inflammatory cytokine production and expression of inflammatory genes. Combined PM and CSE exposure further activated the MAPK and Nrf2 signaling pathways. SFN and SFNAC attenuated CSE/PM-induced epithelial toxicity through the ERK/JNK signaling pathway-dependent inhibition of inflammation. Moreover, SFN and SFNAC suppressed ROS generation by activating antioxidant enzymes and Nrf2 signaling. Therefore, SFN and SFNAC could be a promising approach to prevent or mitigate the exacerbation of pulmonary diseases caused by PM and other air pollutants.

Particulate-Matter Related Respiratory Diseases.

Particulate matter (PM) is suspended dust that has a diameter of <10 µm and can be inhaled by humans and deposited in the lungs, particularly the alveoli. Recent studies have shown that PM has an adverse effect on respiratory diseases. The aim of this article is to review respiratory diseases associated with PM. According to existing studies, PM is associated with chronic obstructive pulmonary disease, bronchial asthma, and several other respiratory diseases and increases the mortality rates of these diseases. Moreover, increased exposure in the high concentration of atmospheric PM is associated with the development of lung cancer. The most simple and common way to protect an individual from airborne PM is to wear a face mask that filters out PM. In areas of high concentration PM, it is recommended to wear a face mask to minimize the exposure to PM. However, the use of N95 or KF94 masks can interfere with respiration in patients with chronic respiratory diseases who exhibit low pulmonary function, leading to an increased risk of respiratory failure. Conclusionally, reduction of the total amount of PM is considered to be important factor and strengthening the national warning notification system to vulnerable patients and proper early management of exacerbated patients will be needed in the future.

Risks of N95 Face Mask Use in Subjects With COPD.

BACKGROUND: The N95 filtering facepiece respirator (FFR) is the most popular individual protective device to reduce exposure to particulate matter. However, concerns have been raised with regard to its use because it can increase respiratory resistance and dead space. Therefore, this study assessed the safety of N95 use in patients with COPD and air-flow limitation. METHODS: This prospective study was performed at a tertiary hospital and enrolled 97 subjects with COPD. The subjects were monitored for symptoms and physiologic variables during a 10-min rest period and 6-min walking test while wearing an N95. RESULTS: Of the 97 subjects, 7 with COPD did not wear the N95 for the entire test duration. This mask-failure group showed higher British modified Medical Research Council dyspnea scale scores and lower FEV1 percent of predicted values than did the successful mask use group. A modified Medical Research Council dyspnea scale score ≥ 3 (odds ratio 167, 95% CI 8.4 to >999.9; P = .008) or a FEV1 < 30% predicted (odds ratio 163, 95% CI 7.4 to >999.9; P = .001) was associated with a risk of failure to wear the N95. Breathing frequency, blood oxygen saturation, and exhaled carbon dioxide levels also showed significant differences before and after N95 use. CONCLUSIONS: This study demonstrated that subjects with COPD who had modified Medical Research Council dyspnea scale scores ≥ 3 or FEV1 < 30% predicted wear N95s only with care.

Exogenous 8-hydroxydeoxyguanosine ameliorates liver fibrosis through the inhibition of Rac1-NADPH oxidase signaling.

BACKGROUND AND AIM: Exogenous 8-hydroxydeoxyguanosine (8-OHdG) was suggested as an inhibitor of Rac1 and NADPH oxidase (NOX). The aim of this study was to evaluate the effects of the exogenous 8-OHdG on hepatic fibrogenesis in vitro and in vivo model of liver fibrosis. METHODS: Adult Sprague-Dawley rats were allocated to sham-operated rats (n = 7), rats that underwent bile duct ligation (BDL) (n = 6), and BDL rats treated with 8-OHdG (60 mg/kg/day by gavage, n = 6). All rats were sacrificed on day 21. Double immunofluorescence staining between either NOX1 or NOX2 and α-smooth muscle actin (SMA) in liver was performed. Hepatic fibrotic contents were assessed by hydroxyproline assay and quantified by Sirius red staining. In vitro, hepatic stellate cell (HSC) line LX-2 and HHSteC cells were stimulated by angiotensin II (10 µM). The reactive oxygen species (ROS) production was measured by confocal microscopy. The expressions of NOX1, NOX2, α-SMA, transforming growth factor (TGF)-ß1, and collagen Iα were analyzed by quantitative real-time polymerase chain reaction or immunoblotting. RESULTS: The 8-OHdG treatment in BDL rats reduced the NOX1 and NOX2 protein expression, which overlapped with α-SMA compared with BDL rats. The 8-OHdG treatment in BDL rats significantly decreased the mRNA expression of NOX1, NOX2, α-SMA, TGF-ß1, and collagen Iα, and fibrotic contents. Increases of ROS production, Rac1 activation, NOX1, NOX2, and fibronectin expression induced by angiotensin II in HSCs were attenuated by 8-OHdG. CONCLUSIONS: Rac1 activation and NOX-derived ROS are implicated to liver fibrosis. The 8-OHdG ameliorates liver fibrosis through the inhibition of Rac1 activation and NOX-derived ROS.