Expression of HCLCA1 in cystic fibrosis lungs is associated with mucus overproduction

Abstract

Mucus overproduction is typical in cystic fibrosis (CF) airway disease. The human calcium-activated chloride channel, hCLCA1, has been reported to be upregulated by interleukin (IL)-9 and to regulate the expression of mucins. Therefore, the expression of IL-9, IL-9 receptor (IL-9R) and hCLCA1 between the lungs of CF patients and healthy control subjects was compared.Endoscopic biopsy samples of bronchial mucosa from 10 CF patients and six control subjects were stained with periodic acid-Schiff. IL-9, IL-9R and hCLCA1 expression was determined by immunocytochemistry. Expression of hCLCA1 mRNA was also determined by in situ hybridisation.The present study found significant increases in IL-9, IL-9R and hCLCA1 immunoreactivity, hCLCA1 mRNA expression, and numbers of mucus-producing cells in the mucosa of CF patients compared to control subjects. Increased expression of interleukin-9 and interleukin-9 receptor, as well as an upregulation of the human calcium-activated chloride channel, hCLCA1, in mucus-producing epithelium of cystic fibrosis patients, support the hypothesis that interleukin-9 contributes to mucus overproduction in cystic fibrosis airway disease.

Mucus hypersecretion: a common symptom, a common mechanism?

“…Hence, in the context of the current understanding of the regulatory process underlying mucus hypersecretion, the findings of HAUBER et al [7] support the possibility that similar mechanisms regulating the increased secretion of mucus are active in both asthma and cystic fibrosis. However, this view remains speculative and awaits confirmation and extension of these findings, but it does move forward the understanding of mucus hypersecretion in the human airways in a further disease state.…”

“…In terms of cystic fibrosis these findings indicate a potentially important component of the host airways defences involved in clinical features and the pathophysiology of cystic fibrosis lung disease. In cystic fibrosis the possible utilisation of alternative chloride channels to cystic fibrosis transmembrane conductance regulator in the airways has been raised previously, but as HAUBER et al [7] speculate the upregulation of the human calcium activated chloride channel-1 gene may not be advantageous in cystic fibrosis, though precise knowledge of the control of mucus hypersecretion may lead to new and innovative treatments in cystic fibrosis, asthma and chronic obstructive pulmonary disease.…”

“…These changes provide a favourable environment for bacterial growth, shelter for bacteria from the host inflammatory response and may reduce the response to systemic antibiotics in patients with chronic pulmonary infection. Therefore, it is of interest that in this issue of the European Respiratory Journal HAUBER et al [7] report on mechanisms linking mucus hypersecretion and airways inflammation in CF. The authors report in bronchial biopsies an increased expression of Interleukin-9 (IL-9), IL-9 receptor and human calcium activated chloride channel-1 (hCLCA1) in bronchial epithelial cells of patients with CF compared with those of healthy subjects.…”

“…Based on the findings of HAUBER et al [7] it may be speculated that in CF, IL-9 may have an isolated mucus hypersecretory effect separate from atopy related mucus hypersecretion, which is considered to have overlapping mechanistic components due to the common mucus hypersecretory effects of IL-9, IL-4 and IL-13. Could IL-9 be acting in an isolated fashion?…”

Hyaluronan Fragments/CD44 Mediate Oxidative Stress–Induced MUC5B Up-Regulation in Airway Epithelium

“…Keywords: MUC5B; hyaluronan fragments; CD44; airway epithelium Mucus overproduction occurs in a variety of acute reactions to cigarette smoke (1) and microorganisms (2,3), as well as in chronic airway inflammatory diseases such as chronic bronchitis (4)(5)(6), asthma (7)(8)(9), bronchiectasis (10), and cystic fibrosis (11). The major macromolecular components of mucus are large and heavily glycosylated mucin proteins that are encoded by various MUC genes (12)(13)(14), that maintain airways homeostasis by protecting the epithelial surface from environmental insults.…”