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A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma

https://doi.org/10.1067/mai.2002.121555Get rights and content

Abstract

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. (J Allergy Clin Immunol 2002;109:246-50.)

Section snippets

Patient profile

Nine asthmatic subjects (mean age, 39 ± 12 years) and 10 healthy nonatopic control subjects (mean age, 40 ± 13 years) were recruited. Asthma severity was assessed on the basis of the Aas scoring system.16 Subjects were excluded if they had a lower respiratory tract infection, an exacerbation of their asthma for up to 8 weeks before the study, or treatment with corticosteroids within 4 months before the study. All subjects were nonsmokers. Approval was obtained from the local ethics committee,

Baseline description of asthmatic subjects compared with healthy control subjects

Asthmatic subjects had significantly increased numbers of major basic protein-immunoreactive eosinophils (23.8 ± 18.4/mm2 of submucosa vs 4.0 ± 4.8/mm2 of submucosa, P < 0.01) and significantly increased number of CD3-immunoreactive T cells (83.7 ± 33.7/mm2 of submucosa vs 51.5 ± 19.3/mm2 of submucosa, P < .05) in the submucosa compared with that seen in normal control subjects. IL-9 immunoreactivity was significantly higher in asthmatic subjects compared with that in healthy control subjects

Discussion

This is the first study that demonstrates the significantly increased expression of HCLCA1 in asthmatic subjects and suggests that this channel is involved in regulating IL-9-dependent mucus gene expressions in asthma. Although the phenomenon of mucus hypersecretion and inflammation have been documented as features of asthma for many years, little is known about their potential relationship. A number of cytokines, including IL-4, IL-13, and IL-9, have been shown, in human asthmatic subjects and

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    Reprint requests: Qutayba Hamid, MD, PhD, Meakins-Christie Laboratories, 3626 St Urbain St, Montreal, Quebec H2X 2P2, Canada.

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