• Tuberculosis and Respiratory Diseases
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• v.81 no.1
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• pp.80-87
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• 2018

Background: Asthma is a disease of chronic airway inflammation with heterogeneous features. Neutrophilic asthma is corticosteroid-insensitive asthma related to absence or suppression of $T_H2$ process and increased $T_H1$ and/or $T_H17$ process. Macrolides are immunomodulatory drug that reduce airway inflammation, but their role in asthma is not fully known. The purpose of this study was to evaluate the role of macrolides in neutrophilic asthma and compare their effects with those of corticosteroids. Methods: C57BL/6 female mice were sensitized with ovalbumin (OVA) and lipopolysaccharides (LPS). Clarithromycin (CAM) and/or dexamethasone (DXM) were administered at days 14, 15, 21, 22, and 23. At day 24, the mice were sacrificed. Results: Airway resistance in the OVA+LPS exposed mice was elevated but was more attenuated after treatment with CAM+DXM compared with the monotherapy group (p<0.05 and p<0.01). In bronchoalveolar lavage fluid study, total cells and neutrophil counts in OVA+LPS mice were elevated but decreased after CAM+DXM treatment. In hematoxylin and eosin stain, the CAM+DXM-treated group showed less inflammation additively than the monotherapy group. There was less total protein, interleukin 17 (IL-17), interferon ${\gamma}$, and tumor necrosis factor ${\alpha}$ in the CAM+DXM group than in the monotherapy group (p<0.001, p<0.05, and p<0.001). More histone deacetylase 2 (HDAC2) activity was recovered in the DXM and CAM+DXM challenged groups than in the control group (p<0.05). Conclusion: Decreased IL-17 and recovered relative HDAC2 activity correlated with airway resistance and inflammation in a neutrophilic asthma mouse model. This result suggests macrolides as a potential corticosteroid-sparing agent in neutrophilic asthma.

• IMMUNE NETWORK
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• v.21 no.4
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• pp.26.1-26.28
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• 2021

Asthma exacerbations are a major cause of intractable morbidity, increases in health care costs, and a greater progressive loss of lung function. Asthma exacerbations are most commonly triggered by respiratory viral infections, particularly with human rhinovirus (hRV). Respiratory viral infections are believed to affect the expression of indoleamine 2,3-dioxygenase (IDO), a limiting enzyme in tryptophan catabolism, which is presumed to alter asthmatic airway inflammation. Here, we explored the detailed role of IDO in the progression of asthma exacerbations using a mouse model for asthma exacerbation caused by hRV infection. Our results reveal that IDO is required to prevent neutrophilic inflammation in the course of asthma exacerbation caused by an hRV infection, as corroborated by markedly enhanced Th17- and Th1-type neutrophilia in the airways of IDO-deficient mice. This neutrophilia was closely associated with disrupted expression of tight junctions and enhanced expression of inflammasome-related molecules and mucin-inducing genes. In addition, IDO ablation enhanced allergen-specific Th17- and Th1-biased CD4⁺ T-cell responses following hRV infection. The role of IDO in attenuating Th17- and Th1-type neutrophilic airway inflammation became more apparent in chronic asthma exacerbations after repeated allergen exposures and hRV infections. Furthermore, IDO enzymatic induction in leukocytes derived from the hematopoietic stem cell (HSC) lineage appeared to play a dominant role in attenuating Th17- and Th1-type neutrophilic inflammation in the airway following hRV infection. Therefore, IDO activity in HSC-derived leukocytes is required to regulate Th17- and Th1-type neutrophilic inflammation in the airway during asthma exacerbations caused by hRV infections.

• Tuberculosis and Respiratory Diseases
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• v.85 no.1
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• pp.18-24
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• 2022

Background: Neutrophilic asthma (NeuA) is usually resistant to corticosteroids. Tiotropium bromide (TIO) is a bronchodilator that is used as an add-on therapy to inhaled corticosteroid and long-acting β2 agonist in asthma treatment. However, the role of TIO in NeuA is not fully known. Thus, the aim of this study was to evaluate the effect of TIO on NeuA compared to that of corticosteroids. Methods: C57BL/6 female mice were sensitized with ovalbumin and lipopolysaccharide to induce neutrophilic inflammation. Dexamethasone (DEX) was administered on days 14, 17, 20, and 23. TIO was inhaled on days 21, 21, and 23. On day 24, mice were sacrificed. Airway hyper-responsiveness, levels of cytokines in bronchoalveolar lavage (BAL) and lung homogenates, and lung tissue histopathology were compared between the two groups. Results: Neutrophil counts, T helper 2 cells (T_H2)/T_H17 cytokines, and pro-inflammatory cytokine in BAL fluids were elevated in the NeuA group. TIO group showed lower total cells, neutrophil counts, and eosinophil counts in BAL fluids than the DEX group (p<0.001, p<0.05, and p<0.001, respectively). Airway resistance was attenuated in the TIO group but elevated in the NeuA group (p<0.001). Total protein, interleukin (IL)-5, and IL-17A levels in BAL fluids were lower in the TIO group than in the NeuA group (all p<0.05). Conclusion: TIO showed more potent effects than DEX in improving airway inflammation and attenuating airway resistance in NeuA.

• Tuberculosis and Respiratory Diseases
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• v.81 no.4
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• pp.350-350
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• 2018

• IMMUNE NETWORK
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• v.22 no.6
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• pp.45.1-45.15
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• 2022

Asthma is a chronic airway inflammatory disease characterized by reversible airway obstruction and airway hyperreactivity to various environmental stimuli, leading to recurrent cough, dyspnea, and wheezing episodes. Regarding inflammatory mechanisms, type 2/eosinophilic inflammation along with activated mast cells is the major one; however, diverse mechanisms, including structural cells-derived and non-type 2/neutrophilic inflammations are involved, presenting heterogenous phenotypes. Although most asthmatic patients could be properly controlled by the guided treatment, patients with severe asthma (SA; classified as a treatment-refractory group) suffer from uncontrolled symptoms with frequent asthma exacerbations even on regular anti-inflammatory medications, raising needs for additional controllers, including biologics that target specific molecules found in asthmatic airway, and achieving the precision medicine for asthma. This review summarizes the immunologic basis of airway inflammatory mechanisms and current biologics for SA in order to address unmet needs for future targets.

• Biomedical Science Letters
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• v.17 no.1
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• pp.89-93
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• 2011

Asthma is an inflammatory airway disease and is characterized by the releases of inflammatory mediators including chemokines. They are mainly associated with the recruitment, activation and dysregulation of specific inflammatory cells, especially neutrophils in neutrophilic asthma. CC chemokines bind to CC chemokine receptors (CCRs) in the surface of their target cells. The aims of this study are to examine the CCR expression in neutrophils of bronchoalveolar lavage fluid (BALF) of asthmatic patients and to determine the alternation of migration and apoptosis of neutrophils by the BALF. We demonstrate that CCR3 strongly expresses in BALF neutrophils of asthmatic patients as compared to other CCRs and increases during apoptosis of the BALF neutrophils. The migration of asthmatic blood neutrophils increases in response to asthmatic BALF as compared to BALF of normal volunteer. In addition, asthmatic BALF includes the higher levels of IL-8 protein than normal BALF and it has no effect on apoptosis of asthmatic blood neutrophils. Taken together, our results indicate that CCR3 expression may be associated with unknown function of asthmatic BALF neutrophils and BALF may be involved in the recruitment of neutrophils into the airway, but not in the neutrophils apoptosis.

• Allergy, Asthma & Immunology Research
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• v.10 no.6
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• pp.614-627
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• 2018

Purpose: Asthma is a heterogeneous disease that responds to medications to varying degrees. Cluster analyses have identified several phenotypes and variables related to fixed airway obstruction; however, few longitudinal studies of lung function have been performed on adult asthmatics. We investigated clinical, demographic, and inflammatory factors related to persistent airflow limitation based on lung function trajectories over 1 year. Methods: Serial post-bronchodilator forced expiratory volume (FEV) 1% values were obtained from 1,679 asthmatics who were followed up every 3 months for 1 year. First, a hierarchical cluster analysis was performed using Ward's method to generate a dendrogram for the optimum number of clusters using the complete post-FEV1 sets from 448 subjects. Then, a trajectory cluster analysis of serial post-FEV1 sets was performed using the k-means clustering for the longitudinal data trajectory method. Next, trajectory clustering for the serial post-FEV1 sets of a total of 1,679 asthmatics was performed after imputation of missing post-FEV1 values using regression methods. Results: Trajectories 1 and 2 were associated with normal lung function during the study period, and trajectory 3 was associated with a reversal to normal of the moderately decreased baseline FEV1 within 3 months. Trajectories 4 and 5 were associated with severe asthma with a marked reduction in baseline FEV1. However, the FEV1 associated with trajectory 4 was increased at 3 months, whereas the FEV1 associated with trajectory 5 was persistently disturbed over 1 year. Compared with trajectory 4, trajectory 5 was associated with older asthmatics with less atopy, a lower immunoglobulin E (IgE) level, sputum neutrophilia and higher dosages of oral steroids. In contrast, trajectory 4 was associated with higher sputum and blood eosinophil counts and more frequent exacerbations. Conclusions: Trajectory clustering analysis of FEV1 identified 5 distinct types, representing well-preserved to severely decreased FEV1. Persistent airflow obstruction may be related to non-atopy, a low IgE level, and older age accompanied by neutrophilic inflammation and low baseline FEV1 levels.