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Selective phosphodiesterase (PDE) inhibitors are a class of nonsteroid anti-inflammatory drugs for treating chronic inflammatory diseases. Modulation of systemic and airway inflammation is their pivotal mechanism of action. Furthermore, PDE inhibitors modulate cough reflex and inhibit airway mucus secretion. Roflumilast, a selective PDE4 inhibitor, has been extensively studied for the efficacy and safety in chronic obstructive pulmonary disease (COPD) patients. According to the mechanisms of action, the potential roles of PDE inhibitors in treating chronic respiratory diseases including severe asthma, asthma-COPD overlap (ACO), noncystic fibrosis bronchiectasis, and chronic cough are discussed. Since roflumilast inhibits airway eosinophilia and neutrophilia in COPD patients, it reduces COPD exacerbations in the presence of chronic bronchitis in addition to baseline therapies. The clinical studies in asthma patients have shown the comparable efficacy of roflumilast to inhaled corticosteroids for improving lung function. However, the clinical trials of roflumilast in severe asthma have been limited. Although ACO is common and is also associated with poor outcomes, there is no clinical trial regarding its efficacy in patients with ACO despite a promising role in reducing COPD exacerbation. Since mucus hypersecretion is a result of neutrophil secretagogue in patients with chronic bronchitis, experimental studies have shown that PDE4s are regulators of the cystic fibrosis transmembrane conductance regulator (CFTR) in human airway epithelial cells. Besides, goblet cell hyperplasia is associated with an increased expression of PDE. Bronchiectasis and chronic bronchitis are considered neutrophilic airway diseases presenting with mucus hypersecretion. They commonly coexist and thus lead to severe disease. The role of roflumilast in noncystic fibrosis bronchiectasis is under investigation in clinical trials. Lastly, PDE inhibitors have been shown modulating cough from bronchodilation, suppressing transient receptors potential (TRP), and anti-inflammatory properties. Hence, there is the potential role of the drug in the management of unexplained cough. However, clinical trials for examining its antitussive efficacy are pivotal. In conclusion, selective PDE4 inhibitors may be potential treatment options for chronic respiratory diseases apart from COPD due to their promising mechanisms of action. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying differences in the susceptibility to chronic obstructive pulmonary disease (COPD) exacerbations between patients are not well understood. Recent studies have shown that the patients with frequent COPD exacerbations is related to specific protein expression in lung tissue. Anterior gradient 3 (AGR3) is expressed in airway epithelial cells in the lung and proteomic analysis revealed that its expression is decreased in patients with frequent COPD exacerbations. Moreover, the loss of epithelial integrity might facilitate trans-epithelial permeability of pathogens in such patients. This study was performed to determine that AGR3 protein play a role in COPD frequency exacerbators. Methods: Human lung tissues were collected from current-smoking patients (Control; n = 15) as well as patients with infrequent COPD exacerbations (IFCOPD; n = 18) and frequent COPD exacerbations (FCOPD; n = 8). While AGR3 protein expression was measured by immunohistochemistry and western blotting, AGR mRNA expression was determined by real time quantitative polymerase chain reaction (RT-qPCR). Furthermore, adherent junctions (AJs) and tight junctions (TJs) protein expression in human lung tissues were measured by immunohistochemistry. The effects of cigarette smoke extract (CSE) on AJ and TJ protein and mRNA expression in BEAS-2B cells were assessed by western blotting and RT-qPCR. In addition, the effect of AGR3 overexpression and knockdown on AJ and TJ protein expression was determined. Results: AGR3 was mainly expressed in the airway epithelium and AGR3-positive products were localized in the cytoplasm. Western blotting and RT-qPCR results showed that AGR3 protein (p = 0.009) and mRNA (p = 0.04) expression in the FCOPD group was significantly lower than that in the IFCOPD group. Moreover, E-cadherin, occludin, and zonula occludens-1 (ZO-1) expression was lower in the FCOPD group than in the IFCOPD group. The protein and mRNA expression of E-cadherin, occludin, and ZO-1 was decreased within 24 h post-CSE exposure. AGR3 overexpression rescued CSE-induced downregulation of E-cadherin, occludin, and ZO-1. Conclusion: Difference in AGR3 expression in the lung tissue might be correlated with increased susceptibility to COPD exacerbation. AGR3 can prevent CSE-induced downregulation of E-cadherin, occludin, and ZO-1 in airway epithelial cells. Loss of AGR3 might promote viral and bacterial infection and induce immune inflammation to increase COPD exacerbation. [ABSTRACT FROM AUTHOR]

Keywords: health status; COPD; (MCID) minimal clinically important difference; St. George's Respiratory Questionnaire; patient-reported outcomes EN health status COPD (MCID) minimal clinically important difference St. George's Respiratory Questionnaire patient-reported outcomes 1 4 4 06/05/20 20200602 NES 200602 Introduction Pharmacological clinical trials require obligatory endpoints in evaluating the clinical relevance of their outcomes ([13]; [17]). The most frequently selected health status instrument in scientific research is the St. George's Respiratory Questionnaire (SGRQ) with a proclaimed MCID of four units on a total scale from 0 to 100 ([11]; [17]; [12]). In a published systematic review in the I European Respiratory Journal i , Alma et al. ([3]) reviewed the available content on the MCID of COPD health status tools including the SGRQ ([3]). Assessing health status over time: impact of recall period and anchor question on the minimal clinically important difference of copd health status tools. [Extracted from the article]

Background: The differential diagnosis in persistent airway limitation is sometimes not so clear in older adults. Airway eosinophilia and airway hyperresponsiveness may develop in some cases with chronic obstructive lung disease (COPD), independent of asthma. However, little is known about clinical significance of these phenotypes of COPD in detail. Aims and objectives: This clinical study was designed to examine prevalence of airway eosinophilia and airway hyperresponsiveness in COPD who have no symptom and no past history of asthma, and to examine involvement of these pathophysiological features of asthma in the management and therapy for COPD. Methods: Sputum examination via qualitative and quantitative procedures was performed in stable COPD (GOLD 1–3). When sputum eosinophils were qualitatively (≥+) or quantitatively assessed (≥3%), ciclesonide (inhaled glucocorticosteroids) was added on bronchodilators. In cases with FEV1 ≥ 70% of predicted values, acetylcholine provocation test was examined for assessment of airway hyperresponsiveness. Therapeutic effect was evaluated using spirometry and COPD assessment test (CAT). Results: Sputum eosinophils were observed in 65 (50.4%) of 129 subjects using qualitative analysis; in contrast, lower grade (>0%) and higher grade (≥3%) were observed in 15 (20.3%) and 25 (33.8%) of 74 subjects using quantitative analysis. Airway hyperresponsiveness developed in 46.9% of these subjects with sputum eosinophils. Exacerbations occurred much more frequently in lower-grade airway eosinophilia without ciclesonide than in higher-grade airway eosinophilia with ciclesonide. Airway hyperresponsiveness significantly increased frequency of exacerbations in COPD with both lower and higher grade in airway eosinophilia. Addition of ciclesonide to indacaterol markedly improved lung function (FEV1, IC), CAT score, and reliever use in these subjects with airway eosinophilia determined by qualitative analysis. However, ciclesonide was less effective in improving these values in subjects with airway hyperresponsiveness than in those without airway hyperresponsiveness. Conclusions: Airway eosinophilia and airway hyperresponsiveness are complicated with 25–50% of COPD that have no symptom and history for asthma. These phenotypes of COPD are closely related to symptom stability and reactivity to glucocorticosteroids. These phenotypes may play key roles for advancement of the management and therapy of this disease. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is the major leading cause of disease with high-mortality worldwide. Cigarette smoke (CS) is a major factor for COPD. CS causes chronic inflammation and oxidative stress, which contributes to lung dysfunction in COPD. Isoliquiritigenin (ILG), a natural flavonoid derived from the root of liquorice, has been reported to possess antiinflammatory and antioxidant activity. In the present study, we tested the mechanism and protective effects of ILG on CS-induced COPD. Mice were exposed to CS for 2 h twice a day for 4 weeks. ILG was given orally 1 h before CS exposure twice a day for 4 weeks. The bronchial alveolar lavage fluid was collected to test the levels of inflammatory cytokines and the number of inflammatory cells. The lung tissues were obtained to evaluate the pathological changes, lung edema, myeloperoxidase (MPO) activity, malondialdehyde (MDA) level, as well as the expression of the nuclear factor-erythroid 2 (Nrf2) and nuclear factor κB (NF-κB) signaling pathways. The results showed that ILG reduced the infiltration of inflammatory cells and the production of inflammatory cytokines. ILG also reversed CS-induced lung pathological injuries, wet/dry ratio, MPO activity, and MDA level. Further research also showed that ILG dose-dependently up-regulated the expression of Nrf2 and down-regulated the expression of NF-κB signaling pathways induced by CS. In conclusion, ILG protected against CS-induced COPD by inhibiting inflammatory and oxidative stress via the regulation of the Nrf2 and NF-κB signaling pathways. [ABSTRACT FROM AUTHOR]

Background: Cigarette smoke exposure (CSE) is a major cause of chronic obstructive pulmonary disease (COPD). The smoke disrupts cell-cell adhesion by inducing epithelial barrier damage to the tight junction (TJ) proteins. Even though the inflammatory mechanism of chemokine (C-C motif) ligand 3 (CCL3) in COPD has gained increasing attention in the research community, however, the underlying signaling pathway, remains unknown. Objectives: To identify the relationship of CCL3 in the pathogenesis of tight junction impairment in COPD and the pathway through which CSE causes damage to TJ in COPD via CCL3, both in vivo and in vitro. Methods: We screened the inflammatory factors in the peripheral blood mononuclear cells (PBMCs) from healthy controls and patients at each GOLD 1-4 stage of chronic obstructive pulmonary disease. RT-PCR, western blot, and ELISA were used to detect the levels of CCL3, ZO-1, and occludin after Cigarette smoke exposure. Immunofluorescence was applied to examine the impairment of the TJs in 16-HBE and A549 cells. The reverse assay was used to detect the effect of a CCR5 antagonist (DAPTA) in COPD. In the CSE-induced COPD mouse model, H&E staining and lung function tests were used to evaluate the pathological and physical states in each group. Immunofluorescence was used to assess the impairment of TJs in each group. ELISA and RT-PCR were used to examine the mRNA or protein expression of CCL3 or miR-4456 in each group. Results: The in vivo and in vitro results showed that CCL3 expression was increased in COPD compared with healthy controls. CCL3 caused significant injury to TJs through its C-C chemokine receptor type 5 (CCR5), while miR-4456 could suppress the effect of CCL3 on TJs by binding to the 3′-UTR of CCL3. Conclusion: miR-4456/CCL3/CCR5 pathway may be a potential target pathway for the treatment of COPD. [ABSTRACT FROM AUTHOR]