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


RESULTS
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.


CONCLUSIONS
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.
Lai
Hon Yee
HY
National Heart & Lung Institute, Imperial College London, UK.
Rogers
Duncan F
DF
D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016503:Drug Delivery Systems; D004358:Drug Therapy; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D020397:Goblet Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D006965:Hyperplasia; D047908:Intracellular Signaling Peptides and Proteins; D009093:Mucus / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology
D047908:Intracellular Signaling Peptides and Proteins; D066246:ErbB Receptors