Thick airway surface liquid volume and weak mucin expression in pendrin-deficient human airway epithelia

Abstract

Pendrin is an anion exchanger whose mutations are known to cause hearing loss. However, recent data support the linkage between pendrin expression and airway diseases, such as asthma. To evaluate the role of pendrin in the regulation of the airway surface liquid (ASL) volume and mucin expression, we investigated the function and expression of pendrin and ion channels and anion exchangers. Human nasal epithelial cells were cultured from 16 deaf patients carrying pendrin mutations (DFNB4) and 17 controls. The cells were treated with IL-13 to induce mucus hypersecretion. Airway surface liquid thickness was measured and real-time polymerase chain reaction was performed targeting various transporters and MUC5AC. Anion exchanger activity was measured using a pH-sensitive fluorescent probe. Periodic acid-Schiff staining was performed on the cultured cells and inferior turbinate tissues. The ASL layer of the nasal epithelia from DFNB4 subjects was thicker than the controls, and the difference became more prominent following IL-13 stimulation. There was no difference in anion exchange activity after IL-13 treatment in the cells from DFNB4 patients, while it increased in the controls. Goblet cell metaplasia induced by IL-13 treatment seen in the controls was not observed in the DFNB4 cells. Furthermore, the periodic acid-Schiff staining-positive area was lesser in the inferior turbinate tissues from DFNB4 patients that those from controls. Pendrin plays a critical role in ASL volume regulation and mucin expression as pendrin-deficient airway epithelial cells are refractory to stimulation with IL-13. Specific blockers targeting pendrin in the airways may therefore have therapeutic potential in the treatment of allergic airway diseases.

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

“…Similar results were found in HBE and CFBE cultures. Quantitative PCR analysis indicated that pendrin transcript levels were increased by 30-to 35-fold in the HBE and CFBE cultures (data not shown), similar to fold increases previously reported in similar cell systems (24,25,35).…”

“…This observation is in agreement with the absence of pendrin function and low pendrin transcript expression found here and in a prior study (24). A prior study that investigated ASL depth homeostasis in airway cell cultures from subjects with pendrin loss-of-function mutations showed that ASL depth was increased by approximately 2-fold compared to cultures derived from control subjects, both without and with IL-13 (35). A possible explanation for the difference in results is that pendrin loss of function in DFNB4 subjects produces compensatory changes in gene expression or protein function that may alter ASL depth homeostasis.…”

“…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).…”

Role of iodide metabolism in physiology and cancer

“…Accordingly, NIS expression has been localized to ciliated columnar cells of the bronchial mucosa, although its precise localization remains controversial (Kang et al 2009). Moreover, ANO1, CFTR, PENDRIN and DUOX2/ DUOX1 are expressed in the Ap membrane of bronchial epithelial cells (Lee et al 2015, Brennan et al 2016, and LPO is secreted primarily in tracheal and bronchial submucosal glands (Wijkstrom-Frei et al 2003). This situation…”

Increased expression of anion transporter SLC26A9 delays diabetes onset in cystic fibrosis

“…Variants in SLC26A9 have been previously associated with atypical CF-like lung disease and risk for asthma (20,21) and modulation of airway response to CFTR-directed therapeutics (22,23). SLC26A9 has been reported to be expressed in epithelial cells of the lung and stomach and multiple other tissues, including salivary gland, heart, skin, kidney, thyroid, and prostate (10,13,(24)(25)(26)(27).…”