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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Antigen challenge and Ca-dependent agonist treatment increased Cl ion transport via the overexpression of TMEM16A in goblet cell metaplasia in a guinea-pig asthma model. TMEM16A inhibitors may be useful for the treatment of hyper-secretion in asthma.

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Exposure to ambient ultrafine particles induces airway inflammatory reactions and tissue remodeling. In this experiment, to determine whether ultrafine carbon black (ufCB) affects proliferation of airway epithelium and, if so, what the mechanism of action is, we studied human primary bronchial epithelial cell cultures. Incubation of cells in the serum-free medium with ufCB increased incorporations of [(3)H]thymidine and [(3)H]leucine into cells in a time- and dose-dependent manner. This effect was attenuated by Cu- and Zn-containing superoxide dismutase (Cu/Zn SOD) and apocynin, an inhibitor of NADPH oxidase, and completely inhibited by pretreatment with the epidermal growth factor receptor (EGF-R) tyrosine kinase inhibitors AG-1478 and BIBX-1382, and the mitogen-activated protein kinase kinase inhibitor PD-98059. Transfection of a dominant-negative mutant of H-Ras likewise abolished the effect ufCB. Stimulation with ufCB also induced processing of membrane-anchored proheparin-binding (HB)-EGF, release of soluble HB-EGF into the medium, association of phosphorylated EGF-R and Shc with glutathione-S-transferase-Grb2 fusion protein, and phosphorylation of extracellular signal-regulated kinase (ERK). Pretreatment with AG-1478, [Glu(52)]Diphtheria toxin, a specific inhibitor of HB-EGF, neutralizing HB-EGF antibody, Cu/Zn SOD, and apocynin each inhibited ufCB-induced ERK activation. These results suggest that ufCB causes oxidative stress-mediated proliferation of airway epithelium, involving processing of HB-EGF and the concomitant activation of EGF-R and ERK cascade.