Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Abstract

Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD.

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

“…Viral vectors, such as adenovirus, lentivirus, retrovirus, Sendai virus or adeno-associated virus, carrying encapsulated siRNA or short hairpin RNA (shRNA) DNA template inserts [110,132,133] can be used to induce RNA interference in cells. Viruses envelopes also contribute to protect siRNA against nucleases and provide a carrier stability.…”

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

“…Pendrin may also be involved in mucus production, a hallmark of airway disease, though the evidence is conflicting. Forced expression of pendrin in cell culture models and the murine lung is associated with elevated mucus production (10), and tissue and cell cultures from DFNB4 subjects show reduced mucus production (35). However, mucus production was not altered in pendrin knockout mice in an asthma model (11).…”

“…IL-13, the cytokine used commonly in in vitro and animal models of airway inflammation, is elevated in CF, asthma, chronic rhinosinusitis, viral and certain bacterial infections, and chronic obstructive pulmonary disease, and in response to cigarette smoke (27)(28)(29)(30)(31)(32)(33)(34). In murine models of asthma, pendrin knockout reduces pulmonary pathology, airway hyperreactivity, and immune cell infiltration, while pendrin overexpression increases airway hyperreactivity (10,11).…”

“…Functional studies show that pendrin mediates electroneutral exchange of Cl 2 with various anions including I 2 , HCO 3 2 , OH 2 , NO 3 2 , SCN 2 (thiocyanate), and HCO 2 2 (formate) (2)(3)(4)(5)(6)(7)(8). In addition to the inner ear and thyroid, pendrin is expressed in the kidney, airways, and adrenal gland (1,4,6,7,(9)(10)(11)(12).…”

“…Pendrin up-regulation is seen in: 1) airway epithelial cultures chronically exposed to cytokines, including IL-4, IL-13, and IL-17A; 2) rodent models of inflammatory lung disease, including allergen (ovalbumin)-induced asthma, chronic obstructive pulmonary disease, infection, and industrial toxin exposure; and 3) humans with rhinovirus infection, asthma, cystic fibrosis (CF), rhinitis, and chronic rhinosinusitis (10,11,(17)(18)(19)(20)(21)(22)(23)(24)(25). Pendrin knockout is also associated with reduced lung inflammation in a murine model of Bordetella pertussis lung infection (26).…”