The Epithelial Anion Transporter Pendrin Is Induced by Allergy and Rhinovirus Infection, Regulates Airway Surface Liquid, and Increases Airway Reactivity and Inflammation in an Asthma Model

Abstract

Asthma exacerbations can be triggered by viral infections or allergens. The Th2 cytokines IL-13 and IL-4 are produced during allergic responses and cause increases in airway epithelial cell mucus and electrolyte and water secretion into the airway surface liquid (ASL). Since ASL dehydration can cause airway inflammation and obstruction, ion transporters could play a role in pathogenesis of asthma exacerbations. We previously reported that expression of the epithelial cell anion transporter pendrin is markedly increased in response to IL-13. Herein we show that pendrin plays a role in allergic airway disease and in regulation of ASL thickness. Pendrin-deficient mice had less allergen-induced airway hyperreactivity and inflammation than did control mice, although other aspects of the Th2 response were preserved. In cultures of IL-13-stimulated mouse tracheal epithelial cells, pendrin deficiency caused an increase in ASL thickness, suggesting that reductions in allergen-induced hyperreactivity and inflammation in pendrin-deficient mice result from improved ASL hydration. To determine whether pendrin might also play a role in virus-induced exacerbations of asthma, we measured pendrin mRNA expression in human subjects with naturally occurring common colds caused by rhinovirus and found a 4.9-fold increase in mean expression during colds. Studies of cultured human bronchial epithelial cells indicated that this increase could be explained by the combined effects of rhinovirus and IFN-γ, a Th1 cytokine induced during virus infection. We conclude that pendrin regulates ASL thickness and may be an important contributor to asthma exacerbations induced by viral infections or allergens.

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

“…Cl 2 /HCO 3 2 exchange is the relevant pendrin function in the airways during inflammatory responses (10,11,26,35). Pendrin-mediated Cl 2 /HCO 3 2 exchange was measured in pendrin-expressing FRT cells using BCECF to report cytoplasmic pH (pH i ) (Fig.…”

“…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). Potential compensatory effects of chronic pendrin loss of function in mice and humans confound clear-cut definition of the roles of pendrin in airway biology.…”

“…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).…”