BACKGROUND: One of the cardinal features of airway remodeling in asthma is mucus gland hyperplasia and mucus overproduction and hypersecretion. Recently, a calcium-activated chloride channel, HCLCA1, was described that is upregulated by IL-9 and thought to regulate the expression of soluble gel-forming mucins, such as MUC5A/C, a critical component of mucus in the airways. OBJECTIVE: We sought to examine the expression of HCLCA1 in bronchial biopsy specimens of asthmatic subjects compared with those of control subjects and to demonstrate its relationship with IL-9, IL-9 receptor (IL-9R), and markers of mucus production. METHODS: Bronchial biopsy specimens from asthmatic (n = 9) and control (n = 10) subjects were stained with periodic acid-Schiff to identify mucus glycoconjugates. IL-9- and IL-9R-positive cells were identified with immunocytochemistry, and HCLCA1 expression was detected by means of in situ hybridization with cRNA probes. RESULTS: We demonstrate significant increases in IL-9 (P <.001) and IL-9R (P <.05) immunoreactivity, as well as increased expression of HCLCA1 mRNA (P <.001), in the epithelium of asthmatic patients compared with that found in control subjects. There was also an increase in the number of mucusproducing cells in biopsy specimens from asthmatic subjects (P <.001). HCLCA1 mRNA was strongly and selectively colocalized with periodic acid-Schiff and IL-9R-positive epithelial cells. In particular, a strong positive correlation was observed between HCLCA1 mRNA expression and IL-9-positive (r = 0.69, P < 0.01) or IL9R-positive (r = 0.79, P <.01) cells. CONCLUSION: An upregulation of HCLCA1 in the IL-9- responsive mucus-producing epithelium of asthmatic subjects compared with that seen in control subjects supports the hypothesis that this channel may be responsible, in part, for the overproduction of mucus in asthmatic subjects. These preliminary findings suggest the inhibition of HCLCA1 may be an important new therapeutic approach to control mucus overproduction in chronic airway disorders.
BACKGROUND: One of the cardinal features of airway remodeling in asthma is mucus gland hyperplasia and mucus overproduction and hypersecretion. Recently, a calcium-activated chloride channel, HCLCA1, was described that is upregulated by IL-9 and thought to regulate the expression of soluble gel-forming mucins, such as MUC5A/C, a critical component of mucus in the airways. OBJECTIVE: We sought to examine the expression of HCLCA1 in bronchial biopsy specimens of asthmatic subjects compared with those of control subjects and to demonstrate its relationship with IL-9, IL-9 receptor (IL-9R), and markers of mucus production. METHODS: Bronchial biopsy specimens from asthmatic (n = 9) and control (n = 10) subjects were stained with periodic acid-Schiff to identify mucus glycoconjugates. IL-9- and IL-9R-positive cells were identified with immunocytochemistry, and HCLCA1 expression was detected by means of in situ hybridization with cRNA probes. RESULTS: We demonstrate significant increases in IL-9 (P <.001) and IL-9R (P <.05) immunoreactivity, as well as increased expression of HCLCA1 mRNA (P <.001), in the epithelium of asthmatic patients compared with that found in control subjects. There was also an increase in the number of mucusproducing cells in biopsy specimens from asthmatic subjects (P <.001). HCLCA1 mRNA was strongly and selectively colocalized with periodic acid-Schiff and IL-9R-positive epithelial cells. In particular, a strong positive correlation was observed between HCLCA1 mRNA expression and IL-9-positive (r = 0.69, P < 0.01) or IL9R-positive (r = 0.79, P <.01) cells. CONCLUSION: An upregulation of HCLCA1 in the IL-9- responsive mucus-producing epithelium of asthmatic subjects compared with that seen in control subjects supports the hypothesis that this channel may be responsible, in part, for the overproduction of mucus in asthmatic subjects. These preliminary findings suggest the inhibition of HCLCA1 may be an important new therapeutic approach to control mucus overproduction in chronic airway disorders.
Authors: Tara Sabo-Attwood; Maria Ramos-Nino; Jeffrey Bond; Kelly J Butnor; Nicholas Heintz; Achim D Gruber; Chad Steele; Douglas J Taatjes; Pamela Vacek; Brooke T Mossman Journal: Am J Pathol Date: 2005-11 Impact factor: 4.307
Authors: Josephine Braun; Melanie K Bothe; Lars Mundhenk; Carol L Beck; Achim D Gruber Journal: Histochem Cell Biol Date: 2009-12-11 Impact factor: 4.304
Authors: Prescott G Woodruff; Homer A Boushey; Gregory M Dolganov; Chris S Barker; Yee Hwa Yang; Samantha Donnelly; Almut Ellwanger; Sukhvinder S Sidhu; Trang P Dao-Pick; Carlos Pantoja; David J Erle; Keith R Yamamoto; John V Fahy Journal: Proc Natl Acad Sci U S A Date: 2007-09-26 Impact factor: 11.205