PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.
PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: 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.
Authors: Jennifer Franko; Laurel G Jackson; Ann Hubbs; Michael Kashon; B J Meade; Stacey E Anderson Journal: Toxicol Sci Date: 2011-10-14 Impact factor: 4.849
Authors: John T Sheridan; Rodney C Gilmore; Michael J Watson; Christopher B Archer; Robert Tarran Journal: J Biol Chem Date: 2013-10-10 Impact factor: 5.157
Authors: Jae Youn Cho; Dae Jae Song; Alexa Pham; Peter Rosenthal; Marina Miller; Shanna Dayan; Taylor A Doherty; Ajit Varki; David H Broide Journal: Respir Res Date: 2010-11-01
Authors: Dale W Porter; Ann F Hubbs; Bean T Chen; Walter McKinney; Robert R Mercer; Michael G Wolfarth; Lori Battelli; Nianqiang Wu; Krishnan Sriram; Stephen Leonard; Michael Andrew; Patsy Willard; Shuji Tsuruoka; Morinobu Endo; Takayuki Tsukada; Fuminori Munekane; David G Frazer; Vincent Castranova Journal: Nanotoxicology Date: 2012-09-13 Impact factor: 5.913