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Background: The considerable prevalence and worse outcomes of asthma-COPD overlap (ACO) in COPD have been reported, and optimal introduction of ICS is essential for ACO. However, diagnostic criteria for ACO consist of multiple laboratory tests, which is challenging during this COVID-19 era. The purpose of this study was to create a simple questionnaire to diagnose ACO in patients with COPD., Methods: Among 100 COPD patients, 53 were diagnosed with ACO based on the Japanese Respiratory Society Guidelines for ACO. Firstly, 10 candidate questionnaire items were generated and further selected by a logistic regression model. An integer-based scoring system was generated based on the scaled estimates of items., Results: Five items, namely a history of asthma, wheezing, dyspnea at rest, nocturnal awakening, and weather- or season-dependent symptoms, contributed significantly to the diagnosis of ACO in COPD. History of asthma was related to FeNO >35 ppb. Two points were assigned to history of asthma and 1 point to other items in the ACO screening questionnaire (ACO-Q), and the area under the receiver operating characteristic curve was 0.883 (95% CI: 0.806-0.933). The best cutoff point was 1 point, and the positive predictive value was 100% at a cutoff of 3 points or higher. The result was reproducible in the validation cohort of 53 patients with COPD., Conclusions: A simple questionnaire, ACO-Q, was developed. Patients with scores ≥3 could be reasonably recommended to be treated as ACO, and additional laboratory testing would be recommended for patients with 1 and 2 points., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Bronchial asthma (BA) is a chronic airway disease characterized by airway hyperresponsiveness and remodeling, which are intimately linked to chronic airway inflammation. Reactive oxygen species (ROS) such as hydrogen peroxide are generated by inflammatory cells that are involved in the pathogenesis of BA. However, the role of ROS in the management of BA patients is not yet clear. We attempted to determine the role of ROS as a biomarker in the clinical setting of BA., Subjects and Methods: We enrolled patients with BA from 2013 through 2015 and studied the degrees of asthma control, anti-asthma treatment, pulmonary function test results, fractional exhaled nitric oxide (FeNO), serum reactive oxygen metabolite (ROM) levels, and serum levels of interleukin (IL)-6 and IL-8., Results: We recruited 110 patients with BA. Serum ROM levels correlated with white blood cell (WBC) count (rs = 0.273, p = 0.004), neutrophil count (rs = 0.235, p = 0.014), CRP (rs = 0.403, p < 0.001), and IL-6 (rs = 0.339, p < 0.001). Serum ROM levels and IL-8 and CRP levels negatively correlated with %FEV1 (rs = -0.240, p = 0.012, rs = -0.362, p < 0.001, rs = -0.197, p = 0.039, respectively). Serum ROM levels were significantly higher in patients who experienced severe exacerbation within 3 months than in patients who did not (339 [302-381] vs. 376 [352-414] CARR U, p < 0.025). Receiver-operating characteristics analysis showed that ROM levels correlated significantly with the occurrence of severe exacerbation (area under the curve: 0.699, 95% CI: 0.597-0.801, p = 0.025)., Conclusions: Serum levels of ROM were significantly associated with the degrees of airway obstruction, WBC counts, neutrophil counts, IL-6, and severe exacerbations. This biomarker may be useful in predicting severe exacerbations of BA., Competing Interests: The authors have declared that no competing interests exist.

Chronic inflammatory airway diseases, such as bronchial asthma and chronic obstructive pulmonary disease, are common respiratory disorders worldwide. Exacerbations of these diseases are frequent and worsen patients' respiratory condition and overall health. However, the mechanisms of exacerbation have not been fully elucidated. Recently, it was reported that interleukin (IL)-17A might play an important role in neutrophilic inflammation, which is characteristic of such exacerbations, through increased production of neutrophil chemoattractants. Therefore, we hypothesized that IL-17A was involved in the pathogenesis of acute exacerbation, due to viral infection in chronic inflammatory airway diseases. In this study, we assessed chemokine production by bronchial epithelial cells and investigated the underlying mechanisms. Comprehensive chemokine analysis showed that, compared with poly(I:C) alone, co-stimulation of BEAS-2B cells with IL-17A and poly(I:C) strongly induced production of such neutrophil chemoattractants as CXC chemokine ligand (CXCL)8, growth-related oncogene (GRO), and CXCL1. Co-stimulation synergistically induced CXCL8 and CXCL1 mRNA and protein production by BEAS-2B cells and normal human bronchial epithelial cells. Poly(I:C) induced chemokine expression by BEAS-2B cells mainly via Toll-like receptor 3/TIR-domain-containing adapter-inducing interferon-β-mediated signals. The co-stimulation with IL-17A and poly(I:C) markedly activated the p38 and extracellular-signal-regulated kinase 1/2 pathway, compared with poly(I:C), although there was little change in nuclear factor-κB translocation into the nucleus or the transcriptional activities of nuclear factor-κB and activator protein 1. IL-17A promoted stabilization of CXCL8 mRNA in BEAS-2B cells treated with poly(I:C). In conclusion, IL-17A appears to be involved in the pathogenesis of chronic inflammatory airway disease exacerbation, due to viral infection by promoting release of neutrophil chemoattractants from bronchial epithelial cells.

Asthma-related mortality has been decreasing due to inhaled corticosteroid use, but severe asthma remains a major clinical problem. One characteristic of severe asthma is resistance to steroid therapy, which is related to neutrophilic inflammation. Recently, the tumor necrosis factor superfamily member (TNFSF) 14/LIGHT has been recognized as a key mediator in severe asthmatic airway inflammation. However, the profiles and intracellular mechanisms of cytokine/chemokine production induced in cells by LIGHT are poorly understood. We aimed to elucidate the molecular mechanism of LIGHT-induced cytokine/chemokine production by bronchial epithelial cells. Human bronchial epithelial cells express lymphotoxin β receptor (LTβR), but not herpesvirus entry mediator, which are receptors for LIGHT. LIGHT induced various cytokines/chemokines, such as interleukin (IL)-6, oncostatin M, monocyte chemotactic protein-1, growth-regulated protein α and IL-8. Specific siRNA for LTβR attenuated IL-6 and IL-8 production by BEAS-2B and normal human bronchial epithelial cells. LIGHT activated intracellular signaling, such as mitogen-activated protein kinase and nuclear factor-κB (NF-κB) signaling. LIGHT also induced luciferase activity of NF-κB response element, but not of activator protein-1 or serum response element. Specific inhibitors of phosphorylation of extracellular signal-regulated kinase (Erk) and that of inhibitor κB attenuated IL-8 production, suggesting that LIGHT-LTβR signaling induces IL-8 production via the Erk and NF-κB pathways. LIGHT, via LTβR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells.

Background: Airway remodeling is implicated in irreversible airflow limitation of refractory asthma, which includes increased smooth muscle mass and subepithelial fibrosis. Activated fibroblasts acquire contractile phenotype to participate in tissue contraction and structural alteration of extracellular matrices. Histamine is a potent mediator of allergic inflammation, substantially involved in asthmatic pathophysiology. Objective: We hypothesized that histamine might play a role in airway remodeling, and investigated its effect on fibroblast-mediated collagen gel contraction. Methods: Fibroblast-mediated collagen gel contraction was studied. Histamine's regulation of collagen gel contraction was characterized by using specific histamine-receptor antagonists, an IP3 receptor antagonist and a PKC inhibitor. Results: Histamine induced contraction of collagen gels embedded with human lung fibroblasts, in a time-dependent manner, and at the concentration more than 10−6 M, both in four primary cultured adult lung fibroblasts and three fetal lung fibroblast cell lines. This effect was attenuated by H1 receptor antagonist, whereas those for H2 to H4 receptors failed to show an inhibitory effect. Furthermore, IP3 receptor-mediated Ca2+ mobilization was implicated in histamine's action on collagen gel contraction. Conclusions: Our results suggest that histamine is involved in airway remodeling through its action on lung fibroblasts, and antihistamine drugs, especially H1 receptor antagonists, might be potentially beneficial for a subset of asthmatic patients. [ABSTRACT FROM AUTHOR]

Background: Airway remodeling is an important feature of chronic airway disease, but the mechanisms involved remain unclear. Recently, epithelial mesenchymal transition (EMT) was reported to be associated with tissue fibrosis. TGF-β1, which is a potent inducer of EMT, is thought to be related to the pathogenesis of airway remodeling. We investigated whether TGF-β1 and/or TNF-α induce EMT in bronchial epithelial cells. Methods: Cultured BEAS-2B cells and primary normal human bronchial epithelial cells (NHBE) were treated with TGF-β1 and/or TNF-α. Morphological changes and the expression of EMT-related markers were evaluated by immunocytochemical staining. Expressions of EMT-related markers, extracellular matrix (ECM) components (collagen type I and versican), and TGF-β receptors I, II, and III were analyzed by quantitative RT-PCR. Migration was evaluated using the Boyden chamber technique. Results: The TGF-β1-induced EMT in BEAS-2B cells was demonstrated on the basis of morphological changes and the downregulation of E-cadherin. Costimulation with TNF-α enhanced the TGF-β1-induced morphological changes and increased vimentin expression. Treatment with TGF-β1 increased the expression of collagen type I and versican. EMT induced with TGF-β1 plus TNF-α promoted cell migration. Stimulation of NHBE with TGF-β1 led to EMT. Conclusion: TGF-β1 induced EMT in BEAS-2B cells, and costimulation with TNF-α enhanced the EMT. As a result of the EMT process, BEAS-2B cells acquired functions of mesenchymal cells. In addition, TGF-β1 treatment induced EMT in NHBE as shown by changes in EMT-related markers. Bronchial epithelial cells might contribute to airway remodeling through EMT. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Fibroblasts, as a major source of extracellular interstitial connective tissue matrix, play an important role in wound healing and the development of fibrosis. The phosphodiesterase (PDE) 4 inhibitor cilomilast inhibits fibroblast chemotaxis and fibroblast-mediated gel contraction. Using the Boyden blindwell chamber chemotaxis assay and the type I collagen gel contraction model, this study investigated whether specific cytokines modulate cilomilast''s inhibitory effect through regulation of endogenous PGE2 production. Human recombinant IL-1β stimulated PGE2 production and shifted the cilomilast concentration–dependence curve to the left in both assay systems, indicating increased sensitivity to cilomilast. In contrast, human recombinant IL-4 inhibited PGE2 production and shifted the cilomilast concentration–dependence curve to the right in both systems. In summary, the inhibitory effect of cilomilast on fibroblast migration and collagen gel contraction is modulated by IL-1β and IL-4 through regulation of PGE2 production. [Copyright &y& Elsevier]