Abstract
The KCa3.1 K+ channel has been proposed as a novel target for pulmonary diseases such as asthma and pulmonary fibrosis. It is expressed in epithelia but its expression and function in primary human bronchial epithelial cells (HBECs) has not been described. Due to its proposed roles in the regulation of cell proliferation, migration, and epithelial fluid secretion, inhibiting this channel might have either beneficial or adverse effects on HBEC function. The aim of this study was to assess whether primary HBECs express the KCa3.1 channel and its role in HBEC function. Primary HBECs from the airways of healthy and asthmatic subjects, SV-transformed BEAS-2B cells and the neoplastic H292 epithelial cell line were studied. Primary HBECs, BEAS-2B and H292 cells expressed KCa3.1 mRNA and protein, and robust KCa3.1 ion currents. KCa3.1 protein expression was increased in asthmatic compared to healthy airway epithelium in situ, and KCa3.1 currents were larger in asthmatic compared to healthy HBECs cultured in vitro. Selective KCa3.1 blockers (TRAM-34, ICA-17043) had no effect on epithelial cell proliferation, wound closure, ciliary beat frequency, or mucus secretion. However, several features of TGFβ1-dependent epithelial-mesenchymal transition (EMT) were inhibited by KCa3.1 blockade. Treatment with KCa3.1 blockers is likely to be safe with respect to airway epithelial biology, and may potentially inhibit airway remodelling through the inhibition of EMT.
Highlights
Asthma is a common disease affecting 5–10% of Westernised populations, and an important cause of morbidity and mortality at all ages [1]
Human bronchial epithelial cells express KCa3.1 mRNA and protein qPCR was performed on primary human bronchial epithelial cell (HBEC) cell monolayers
HBEC, H292 and BEAS-2B lysates contained an immunoreactive protein of approximately 48 kDa, the predicted size of KCa3.1 [37]]
Summary
Asthma is a common disease affecting 5–10% of Westernised populations, and an important cause of morbidity and mortality at all ages [1]. For approximately 10% of patients with asthma, current therapies are of poor efficacy: in consequence novel approaches to treatment are urgently required. Ion channels are emerging as interesting therapeutic targets in both inflammatory and structural non-excitable cells. Channels carrying K+, Cl-, and Ca2+ mediate a variety of cell processes including proliferation [2], differentiation [3], adhesion [4], mediator release [5] and migration [6]. The Ca2+-activated K+ channel KCa3.1 is of particular interest as a novel target for asthma therapy [7,8,9]. The airway epithelium is at the interface between the airway and the external environment, and is the first structure to interact with noxious stimuli such as allergens, viruses and PLOS ONE | DOI:10.1371/journal.pone.0145259. The airway epithelium is at the interface between the airway and the external environment, and is the first structure to interact with noxious stimuli such as allergens, viruses and PLOS ONE | DOI:10.1371/journal.pone.0145259 December 21, 2015
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