Airway Mucus Hypersecretion In Asthma Research Articles

Rho-kinase inhibitor fasudil reduces allergic airway inflammation andmucus hypersecretion by regulating STAT6 and NFκB.

Airway mucus hypersecretion is a key pathophysiological feature in asthma. Fasudil, a selective Rho-A/Rho kinase inhibitor, has been used in clinical trials to treat pulmonary hypertension. However, its function in modulating airwaymucushypersecretion in asthma remains undefined. We examined whether fasudil, a selective Rho-A/Rho kinase inhibitor, affects the mucus hypersecretion by suppressing MUC5AC via signal transducer and activator of transcription factor 6 (STAT6) and nuclear factor-kappa B (NFκB) in mice and cells. We measured mucus secretion and the expression of Rho-kinase in the airway tissue of patients with asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA) followed with fasudil treatment. The lung tissues were assessed for airway inflammation and mucus secretion. Cytokine levels and airway responsiveness were determined. STAT6 and NFκB were quantified by Western blot. 16HBE cells were stimulated with house dust mite (HDM) extracts. MUC5AC and muc5ac promoter activities were measured. Using siRNA to knockdown STAT6 in epithelial cells, we determined the impact of STAT6 on muc5ac promoter activity. NFκB nuclear translocation was observed with immunostaining. Fasudil administration significantly decreased the number of inflammatory cells, inflammation index in the lung and airway responsiveness. Fasudil also reduced mucous secretion and MUC5AC expression in OVA-challenged mice. Fasudil down-regulated the levels of IL-17, IL-4 and IL-13 in the lung tissue of OVA-challenged mice. Fasudil also decreased the expression and phosphorylation of NFκB and STAT6 as well as the nuclear translocation of NFκB. In addition, human airway epithelial cells (16HBE) were challenged with HDM extracts and then treated with fasudil. Fasudil inhibited HDM extract-induced MUC5AC expression, which is associated with a reduction in STAT6 and NFκB in epithelial cells. These findings indicate that the Rho-A/Rho kinase inhibitor, fasudil, plays a negative regulatory role in allergen-induced mucus secretion and MUC5AC expression by regulating STAT6 and NFκB.

Notch Signaling Downregulates MUC5AC Expression in Airway Epithelial Cells through Hes1-Dependent Mechanisms

Background: Mucus overproduction is one of the major pathological features of asthma, and MUC5AC is the major mucin component of airway mucus. However, whether Notch signaling is implicated in the regulation of MUC5AC expression in airway secretary cells is still undetermined. Objective: The aim of this study is to examine whether Notch signaling can regulate MUC5AC expression and explore the molecular mechanisms. Methods: Mouse mtCC1-2 cells and human NCI-H292 cells were transfected with NIC, and MUC5AC expression was examined. Using gene reporter assays, site-directed mutagenesis, and ChIP assays, the activity of both mouse and human MUC5AC promoter was analyzed. Results: Notch signaling regulated MUC5AC expression both in mouse mtCC1-2 cells and in human NCI-H292 cells. Several Hes-binding site N-boxes were identified in the 5′ region of both mouse and human MUC5AC promoters. Overexpression of NIC resulted in activation of the MUC5AC promoter. Site-directed mutagenesis report assays revealed that Hes proteins might repress both mouse and human MUC5AC promoter activity. Furthermore, ChIP assays confirmed that Hes1 binds to the MUC5AC promoter both in mouse mtCC1-2 cells and in human NCI-H292 cells. Conclusions: Notch signaling can directly downregulate MUC5AC promoter activity through Hes1-dependent mechanisms, which may be identified as possible targets for pharmacotherapy of airway mucus hypersecretion in asthma.

Small-airways deposition of dornase alfa in children with asthma and persistent airway obstruction

Small-airways deposition of dornase alfa in children with asthma and persistent airway obstruction

New Pharmacotherapy for Airway Mucus Hypersecretion in Asthma and COPD: Targeting Intracellular Signaling Pathways

Airway mucus hypersecretion is a pathophysiological feature of asthma and chronic obstructive pulmonary disease (COPD). The hypersecretion is associated with phenotypic changes in the airways, notably, increases in the number of surface epithelial goblet cells (hyperplasia) and in the size of the submucosal glands (hypertrophy). The hyperplasia and hypertrophy are associated with increased production of mucin, the gel-forming component of mucus. The excess mucus production contributes to morbidity and mortality in many patients, particularly in those with more severe disease. Although current pharmacotherapy is effective in clinical management of patients with stable asthma, severe asthma is poorly treated and there is no current drug treatment for COPD. In neither disease is there specific, effective pharmacotherapy for the hypersecretion. Consequently, identification of potential drug targets for treatment of hypersecretion in asthma and COPD is warranted. The inflammatory mediators and the associated intracellular signaling pathways underlying upregulation of mucin synthesis and development of goblet cell hyperplasia are gradually being elucidated. These include Th2 cytokines (predominantly IL-9 and IL-13), and IL-1 beta, tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase (COX)-2. IL-9 may act predominantly via calcium-activated chloride channels (CLCA), IL-13 via STAT-6 and FOXA2, TNF-alpha via NF-kappaB, and IL-1 beta via COX-2. Epidermal growth factor receptor (EGF-R) signaling and FOXA2 appear to be convergent intracellular pathways for a number of inflammatory mediators, with EGF-R upregulated in the airways of asthmatic and COPD patients. Thus, preclinical studies have clearly identified a number of intracellular signaling pathways as possible targets for pharmacotherapy of airway mucus hypersecretion in asthma and COPD. Of these, the EGF-R and Th2 cytokine pathways may have the greatest potential for inhibition of excessive mucus production. However, because these targets are so often intimately involved with different aspects of airway (and systemic) homeostasis, there is potential for development of unwanted side effects with drug intervention. Thus, translation of the promising preclinical studies to the clinic will depend on development of drug moieties with low off-target activity. This may be accomplished by maximizing airway selectivity, which may be facilitated by appropriate delivery device design.

Mucus hypersecretion in asthma: intracellular signalling pathways as targets for pharmacotherapy

Airway mucus hypersecretion is a pathophysiological feature of asthma and, in many patients, contributes to morbidity and mortality. Although current pharmacotherapy is effective in patients with stable disease, severe asthma is poorly treated, and there is no specific treatment for the hypersecretion. Consequently, identification of potential targets for pharmacotherapy of hypersecretion in asthma is warranted. This review identifies intracellular signalling pathways as rational targets for treatment of excessive airway mucus production. The inflammatory mediators and the associated intracellular signalling pathways underlying development of goblet cell hyperplasia, an index of mucus hypersecretion, are becoming ever clearer, and include T-helper type 2 (Th2) cytokines, in particular interleukin (IL)-9 and IL-13, as well as IL-1beta, tumour necrosis factor (TNF)-alpha and cyclooxygenase (COX)-2. IL-9 may act predominantly via calcium-activated chloride channels (CLCAs), IL-13 via STAT-6 and FOXA2, TNF-alpha via nuclear factor (NF)-kappaB, and IL-1beta via COX-2. Epidermal growth factor receptor (EGF-R) and FOXA2 appear to be convergent pathways for a number of mediator signals, with EGF-R up-regulated in the airways of asthmatic patients. Although many potential intracellular signalling pathways have been identified as possible targets for pharmacotherapy of airway mucus hypersecretion in asthma, the EGF-R and Th2 cytokine pathways offer the greatest potential for inhibition of excessive mucus production.

Airway mucus hypersecretion in asthma: an undervalued pathology?

Airway mucus hypersecretion is a feature of many patients with asthma. It is indicative of poor asthma control and contributes to morbidity and mortality. Excess mucus not only obstructs airways but also contributes to airway hyperresponsiveness. Furthermore, asthma might have a specific mucus hypersecretory phenotype. Goblet cell hyperplasia and submucosal gland hypertrophy are shared with other hypersecretory diseases, such as chronic obstructive pulmonary disease; however, some features are different, including mucus plugging, mucus "tethering" to goblet cells, plasma exudation, and increased amounts of a low charge glycoform of mucin (MUC)5B and the presence of MUC2 in secretions. Experimentally, most of the inflammatory mediators and neural mechanisms implicated in the pathophysiology of asthma impact upon the mucus hypersecretory phenotype. There is currently huge research interest in identifying targets involved in inducing mucus abnormalities, which should lead to the rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma.