Explore the vast range of titles available.

In COPD, the activity of the cholinergic system is increased, which is one of the reasons for the airflow limitation caused by the contraction of airway smooth muscles. Therefore, blocking the contractive actions with anticholinergics is a useful therapeutic intervention to reduce the airflow limitation. In addition to the effects of bronchoconstriction and mucus secretion, accumulating evidence from animal models of COPD suggest acetylcholine has a role in inflammation. Experiments using muscarinic M -receptor deficient mice or M selective antagonists revealed that M -receptors on parenchymal cells, but not on hematopoietic cells, are involved in the pro-inflammatory effect of acetylcholine. Recently, combinations of long-acting β2 adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have become available for COPD treatment. These dual long-acting bronchodilators may have synergistic anti-inflammatory effects because stimulation of β2 adrenergic receptors induces inhibitory effects in inflammatory cells via a different signaling pathway from that by antagonizing M -receptor, though these anti-inflammatory effects have not been clearly demonstrated in COPD patients. In contrast to the pro-inflammatory effects by ACh via muscarinic receptors, it has been demonstrated that the cholinergic anti-inflammatory pathway, which involves the parasympathetic nervous systems, regulates excessive inflammatory responses to protect organs during tissue injury and infection. Stimulation of acetylcholine via the α7 nicotinic acetylcholine receptor (α7nAChR) exerts inhibitory effects on leukocytes including macrophages and type 2 innate lymphoid cells. Although it remains unclear whether the inhibitory effects of acetylcholine via α7nAChR in inflammatory cells can regulate inflammation in COPD, neuroimmune interactions including the cholinergic anti-inflammatory pathway might serve as potential therapeutic targets.

Despite standard treatment with systemic corticosteroids and/or antifungal triazoles, a substantial proportion of patients with allergic bronchopulmonary aspergillosis (ABPA) experience frequent relapses and require long-term treatment despite unfavorable adverse effects. We investigated the efficacy and safety of anti-interleukin (IL)-5/IL-5 receptor α chain (Rα) monoclonal antibodies (mAbs) in patients with ABPA complicated by asthma. ABPA cases treated with anti-IL-5/IL-5Rα mAbs were collected from 132 medical institutes in 2018 and published case reports in Japan. Clinical outcomes, laboratory and physiological data, and radiographic findings during 32 weeks before and after treatment were retrospectively evaluated. We analyzed 29 cases of ABPA: 20 treated with mepolizumab and nine with benralizumab. Treatment with anti-IL-5/IL-5Rα mAbs reduced the frequency of exacerbations ( p  = 0.03), decreased the dose of oral corticosteroids ( p  < 0.01), and improved pulmonary function ( p  = 0.01). Mucus plugs in the bronchi shrank or diminished in 18 patients (82%). Despite the clinical/radiographical improvement, serum levels of total IgE, the key biomarker for the pharmacological response in ABPA, were unchanged. Anti-IL-5/IL-5Rα mAbs that directly target eosinophils are promising candidates for the treatment of patients with ABPA, especially those with mucus plugs in the bronchi.

Axl receptor tyrosine kinase is involved in the growth and metastasis and is an indicator of poor prognosis in several cancers including lung cancers. Although a mitogen-activated protein kinase (MAPK) pathway and an epithelial-to-mesenchymal transition (EMT) program are critical, molecular mechanisms underlying the Axl-driven cancer progression have not been fully elucidated. We aimed to identify molecules up-regulated by Axl kinase in lung adenocarcinomas. Through the global gene expression analysis and the functional annotation clustering, we found that AXL expression positively correlated with mRNA expressions of immune checkpoint molecules and chemokine receptors in non-small-cell lung cancers. Validation cohorts including our biobank confirmed that the AXL expression significantly correlated with expression of genes encoding programmed death-ligand1 (PD-L1) and CXC chemokine receptor 6 (CXCR6) in lung adenocarcinoma, especially in epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma. Pharmacological inhibition of Axl kinase activity decreased mRNA expressions of PD-L1 and CXCR6 in EGFR mutation-positive cell lines. Our data indicates the novel role of Axl kinase as a driver of immune checkpoint molecules and chemokine signalling pathways in the progression of lung adenocarcinomas. This study also highlights the necessity of clinical trials in order to test the efficacy of Axl kinase inhibition in the Axl-highly expressing subset of lung adenocarcinomas.

Background Recently, the addition of inhaled corticosteroid (ICS) to long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist (LABA) combination therapy has been recommended for patients with COPD who have severe symptoms and a history of exacerbations because it reduces the exacerbations. In addition, a reducing effect on mortality has been shown by this treatment. However, the evidence is mainly based on one large randomized controlled trial IMPACT study, and it remains unclear whether the ICS add-on treatment is beneficial or not. Recently, a large new ETHOS trial has been performed to clarify the ICS add-on effects. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety including ETHOS trial. Methods We searched relevant randomized control trials (RCTs) and analyzed the exacerbations, quality of life (QOL), dyspnea symptom, lung function and adverse events including pneumonia and mortality, as the outcomes of interest. Results We identified a total of 6 RCTs in ICS add-on protocol (N = 13,579). ICS/LAMA/LABA treatment (triple therapy) significantly decreased the incidence of exacerbations (rate ratio 0.73, 95% CI 0.64–0.83) and improved the QOL score and trough FEV 1 compared to LAMA/LABA. In addition, triple therapy significantly improved the dyspnea score (mean difference 0.33, 95% CI 0.18–0.48) and mortality (odds ratio 0.66, 95% CI 0.50–0.87). However, triple therapy showed a significantly higher incidence of pneumonia (odds ratio 1.52, 95% CI 1.16–2.00). In the ICS-withdrawal protocol including 2 RCTs, triple therapy also showed a significantly better QOL score and higher trough FEV 1 than LAMA/LABA. Concerning the trough FEV 1 , QOL score and dyspnea score in both protocols, the differences were less than the minimal clinically important difference. Conclusion Triple therapy causes a higher incidence of pneumonia but is a more preferable treatment than LAMA/LABA due to the lower incidence of exacerbations, higher trough FEV 1 and better QOL score. In addition, triple therapy is also superior to LABA/LAMA due to the lower mortality and better dyspnea score. However, these results should be only applied to patients with symptomatic moderate to severe COPD and a history of exacerbations. Clinical Trial Registration: PROSPERO; CRD42020191978.

Supersulphides are inorganic and organic sulphides with sulphur catenation with diverse physiological functions. Their synthesis is mainly mediated by mitochondrial cysteinyl-tRNA synthetase (CARS2) that functions as a principal cysteine persulphide synthase (CPERS). Here, we identify protective functions of supersulphides in viral airway infections (influenza and COVID-19), in aged lungs and in chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF). We develop a method for breath supersulphur-omics and demonstrate that levels of exhaled supersulphides increase in people with COVID-19 infection and in a hamster model of SARS-CoV-2 infection. Lung damage and subsequent lethality that result from oxidative stress and inflammation in mouse models of COPD, IPF, and ageing were mitigated by endogenous supersulphides production by CARS2/CPERS or exogenous administration of the supersulphide donor glutathione trisulphide. We revealed a protective role of supersulphides in airways with various viral or chronic insults and demonstrated the potential of targeting supersulphides in lung disease. The physiological roles of supersulphides and the enzymes that trigger their production in various airway diseases are not fully understood. Here, the authors show in animal models of viral and chronic lung diseases that supersulphide production can mitigate lung pathology and lethal effects, highlighting their protective role and potential as a therapeutic target.

Background Alveolar macrophages are professional phagocytes that remove microbial pathogens inhaled into the lung. The phagocytic ability is compromised in chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms underlying this defect in phagocytosis are not clearly defined. Materials and methods Cell suspensions were collected from lung tissues of patients undergoing lung resection. Alveolar macrophages were detected as FSC hi / SSC hi /CD45 + /CD206 + cells in the isolated cell suspension by flow-cytometry. The cell surface expression of plasma membrane-bound phagocytic receptors (Fcγ receptor I (FcγRI), a complement receptor CD11b, macrophage scavenger receptor-1 (MSR-1), CD36 and Siglec-1) was determined on the alveolar macrophages. Correlations between the expression levels of the phagocytic receptors and disease severity were analysed. Phagocytosis of fluorescence-tagged bacteria by human alveolar macrophages was evaluated. Results The flow-cytometry analyses revealed that FcγRI, CD11b, MSR-1 and Siglec-1, but not CD36, were expressed on human alveolar macrophages. Among these receptors, Siglec-1 expression was significantly decreased on alveolar macrophages in COPD ex-smokers ( n  = 11), compared to control never-smokers (n = 11) or control ex-smokers ( n  = 9). The Siglec-1 expression on alveolar macrophages was significantly correlated with lung function (forced expiratory volume in 1 s) and with the severity of emphysema. Treatment of human alveolar macrophages with an anti-Siglec1 blocking antibody decreased phagocytosis of non-typeable Haemophilus influenzae (NTHi). Conclusion Our findings demonstrated reduced expression of Siglec-1 on alveolar macrophages in COPD, which is involved in engulfment of NTHi.

Background Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, and its possible involvement in the pathophysiology of COPD and viral-induced exacerbations has been demonstrated. IL-33 has been shown to be increased in the airway epithelial cells from COPD patients, but the regulating mechanism of IL-33 expression in airway epithelial cells remains largely unknown. In the current study, we examined whether oxidative stress, which participates in the pathogenesis of COPD, affects the expression of IL-33 in airway epithelial cells and also evaluated the effect during viral infection. Methods The involvement of oxidative stress in the expression of IL-33, and its signal pathway was examined after stimulation with hydrogen peroxide (H 2 O 2 ), with or without stimulation by polyinosinic-polycytidylic acid [poly (I:C)], a synthetic analogue of dsRNA that mimics viral infection, or rhinovirus infection in NCI-H292 cells and primary human bronchial epithelial cells (HBECs). In addition, the effect of antioxidant, N -acetylcysteine (NAC) in the expression of IL-33 was compared between HBECs from healthy subjects and those from COPD patients. Results Treatment with H 2 O 2 significantly potentiated IL-33 expression in NCI-H292 cells, and the potentiation was reversed by NAC treatment. Mitogen-activated protein kinase (MAPK) inhibitors, but not nuclear factor-kappa B inhibitors, also significantly decreased the H 2 O 2 -potentiated IL-33 expression. In addition, H 2 O 2 significantly potentiated the poly (I:C)- or rhinovirus-stimulated IL-33 expression. In HBECs from healthy subjects, H 2 O 2 -potentiated IL-33 expression and its reversal by NAC was also confirmed. Under the condition without H 2 O 2 -stimulation, treatment with NAC significantly decreased the expression of IL-33 in HBECs from COPD patients, but not in those from healthy subjects. Conclusions These results demonstrate that oxidative stress involves in the expression of IL-33 in airway epithelial cells via MAPK signal pathway and it augments IL-33 expression during viral infection. This mechanism may participate in the regulation of IL-33 expression in airway epithelial cells in COPD and the viral-induced exacerbations. Modulation of this pathway could become a therapeutic target for viral-induced exacerbations of COPD.

Background Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis. Although the median survival is 3 years, the clinical course varies to a large extent among IPF patients. To date, there has been no definitive prognostic marker. Extracellular vesicles (EVs) are known to hold nucleic acid, including microRNAs, and to regulate gene expression in the recipient cells. Moreover, EVs have been shown to express distinct surface proteins or enveloped microRNAs depending on the parent cell or pathological condition. We aimed to identify serum EV microRNAs that would be prognostic for IPF. Methods To determine target microRNAs in IPF, we measured serum EV microRNA expression profiles using microRNA PCR arrays in a bleomycin mouse model and validated the microRNAs in additional mice using RT-PCR. Secondly, we enrolled 41 IPF patients and conducted a 30-month prospective cohort study. Expression of serum EV miR-21-5p was normalized by dividing by the EV amount. The relative amount of EVs was measured using the ExoScreen method. We calculated the correlations between baseline serum EV miR-21-5p expression and other clinical variables. Furthermore, we determined if serum EV miR-21-5p can predict mortality during 30 months using the Cox hazard model. According to the median level, we divided the IPF patients into two groups. Then we compared the survival rate during 30 months between the two groups using the Kaplan-Meier method. Results Serum EV miR-21-5p was elevated in both the acute inflammatory phase (day 7) and the chronic fibrotic phase (day 28) in the mouse model. In the clinical setting, serum EV miR-21-5p was significantly higher in IPF patients than in healthy control subjects. The baseline serum EV miR-21-5p was correlated with the rate of decline in vital capacity over 6 months. Furthermore, serum EV miR-21-5p was independently associated with mortality during the following 30 months, even after adjustment for other variables. In the survival analysis, IPF patients whose baseline serum EV miR-21-5p was high had a significantly poorer prognosis over 30 months. Conclusions Our results suggest that serum EV miR-21-5p has potential as a prognostic biomarker for IPF.

Background Inhaled bronchodilators including long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) play a central role in the treatment of stable chronic obstructive pulmonary disease (COPD). However, it is still unclear whether LABA or LAMA should be used for the initial treatment. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of LABA versus LAMA in patients with stable COPD. Methods We searched relevant randomized control trials (RCTs) with a period of treatment of at least 12 weeks and analyzed the exacerbations, quality of life, dyspnea score, lung function and adverse events as the outcomes of interest. Results We carefully excluded unblinded data and identified a total of 19 RCTs ( N  = 28,211). LAMA significantly decreased the exacerbations compared to LABA (OR 0.85, 95% CI 0.74 to 0.98; P  = 0.02). In St George’s Respiratory Questionnaire and transitional dyspnoea index score, there were no differences between LABA and LAMA treatment. Compared to LABA, there was a small but significant increase in the trough FEV 1 after LAMA treatment (Mean difference 0.02, 95% CI 0.01 to 0.03, P  = 0.0006). In the safety components, there was no difference in the serious adverse events between LABA and LAMA. However, LAMA showed a significantly lower incidence of total adverse events compared to LABA (OR 0.92, 95% CI 0.86 to 0.98; P  = 0.02). Conclusion Treatment with LAMA in stable COPD provided a significantly lower incidence of exacerbation and non-serious adverse events, and a higher trough FEV 1 compared to LABA. Trial registration (PROSPERO: CRD42019144764 )

BackgroundOxidative stress is a major aetiological factor driving chronic obstructive pulmonary disease (COPD). Recently recognised as potent antioxidants, reactive persulfide and polysulfide species are biosynthesised by cystathionine β-synthase and cystathionine γ-lyase. The production of reactive persulfide and polysulfide species in the lungs of patients with COPD remain unknown.ObjectivesThe aim of this study was to examine the production of reactive persulfides and polysulfides, such as glutathione persulfide (GSSH), cysteine persulfide (CysSSH) and glutathione trisulfide (GSSSH), in lung-resident cells and epithelial lining fluid (ELF) obtained from patients with mild to moderate COPD.MethodsLung tissues, primary lung cells, ELF and sputum were obtained. The amounts of reactive persulfides and polysulfides in the cells and ELF were measured by liquid chromatography–tandem mass spectrometry with β-(4-hydroxyphenyl) ethyl iodoacetamide as a trapping agent for hydroper/polysulfides. The amounts of synthases in the lung tissues, sputum and primary cells were quantified.ResultsThe amounts of GSSH, CysSSH and GSSSH were decreased in the lung cells and ELF from patients with COPD. The amounts of reactive persulfides and polysulfides in the lung cells had a positive correlation with the degree of airflow limitation. By contrast, the amounts of the synthases were increased in the lung tissues and sputum cells of patients with COPD.ConclusionsWe have identified a decrease in reactive persulfide and polysulfide species in the lungs of patients with COPD. These data suggest that the newly detected antioxidants reactive persulfides and polysulfides could be associated with the redox balance in the lungs of patients with COPD.