Asthma is a chronic inflammatory disease characterized by reversible airflow limitation and airway hyperresponsiveness. Persistent inflammation in airway tissues may lead to structural changes known as airway remodeling and consequently airway obstruction that is not fully reversible and progressive loss of lung function over time. It is generally accepted that airway remodeling is closely related to progression of airway hyperresponsiveness, and the severity of asthma. The structural changes observed in chronic persistent asthma, which includes airway smooth muscle hypertrophy and hyperplasia, collagen deposition to sub-epithelial basement membrane, hyperplasia of goblet cells, thickening of airway mucosa and an increase in vascularity, are derived from airway inflammation. For instance, the thickened airway mucosa might be produced by cytokines and growth factors released from inflammatory cells and airway epithelial cells, and associated with bronchial hyperreactivity and asthma severity. To date, many studies have identified candidate mechanisms and mediators for these observed structural changes, which are thus potential targets in the treatment of asthma. In this review, we describe the recent knowledge of the mechanisms and clinical implications of airway remodeling in asthma.

Macrolide antibiotics possess a variety of actions other than antimicrobial activities. To determine the effects of long-term administration of clarithromycin (CAM) on the amount and physical properties of sputum in patients with clinical conditions associated with excessive airway secretions, we conducted the present study in a parallel, double-blind, placebo-controlled fashion. Patients were divided into two groups: the first group (n ‫؍‬ 16) received CAM (100 mg, twice a day) for 8 weeks, and the second group (n ‫؍‬ 15) received placebo. In evaluating airway secretion, the daily amount of expectorated sputum, solid composition, viscoelastic properties (including elastic modulus and dynamic viscosity), and sputum microbiology were assessed. CAM decreased sputum production from 51 ؎ 6 to 24 ؎ 3 g/day after treatment, whereas placebo had no effect. The bacterial density and sputum flora were unaltered. In the group receiving CAM, the percent solid composition and elastic modulus increased from 2.44% ؎ 0.29% to 3.01% ؎ 0.20% and 66 ؎ 7 to 87 ؎ 8 dyne/cm 2 (P < 0.05), respectively, but the dynamic viscosity remained unchanged. These results suggest that long-term treatment with CAM reduces the amount of sputum production, probably by inhibiting airway secretions, and increases sputum elasticity.There is increasing evidence that long-term administration of the macrolide antibiotic erythromycin is effective in the treatment of chronic respiratory infections, probably through actions other than its antimicrobial properties (6). Although the mechanism of the efficacy is uncertain, several hypotheses have been proposed, such as immunomodulatory action on inflammatory cells (1,8), inhibition of glycoconjugate secretion from submucosal glands (3), and inhibition of airway epithelial chloride transport and the concomitant secretion of water (12). However, the effects of newly developed macrolides on airway secretion are unknown. Therefore, to investigate whether longterm treatment with oral clarithromycin (CAM) alters sputum production and its rheological properties, we conducted a placebo-controlled trial with a group of patients with chronic bronchitis, bronchiectasis, or diffuse panbronchiolitis. Diffuse panbronchiolitis is a recently described clinicopathologic condition which is found in Japanese, Chinese, and Korean populations and which is characterized by severe, chronic airflow limitation and excessive sputum production accompanied by persistent sinopulmonary infection, respiratory bronchiolitis, and peribronchiolitis (4). MATERIALS AND METHODSPatients. Thirty-one patients, 33 to 77 years of age, who had chronic bronchitis, bronchiectasis, or diffuse panbronchiolitis and who had been continuously expectorating more than 30 g of sputum per day for at least 2 weeks prior to the study were selected after their consent was obtained. All cases of chronic bronchitis conformed to the World Health Organization's definition of the disease (15), and all patients with chronic bronchitis were or had been heavy smokers. Bronc...

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Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.