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• W2117164023 abstract "Airway surface liquid (ASL) homeostasis, achieved by balancing transepithelial fluid absorption and secretion, is essential for mucociliary clearance and to prevent inundation (e.g. pulmonary oedema) or dehydration (e.g. cystic fibrosis (CF)) of the respiratory airways. Current models of ion transport by large airways (e.g. bronchi and trachea) suggest that ASL volume is controlled by ciliated cells in the surface epithelium, which oscillate between absorptive and secretory states orchestrated by two apical membrane ion channels, the epithelial sodium channel (ENaC) and the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, respectively, (Boucher, 2007). Such models of ASL regulation deviate from the classical paradigm of ion transport by most other epithelial tissues, including the intestine, pancreas, salivary and sweat glands, where cells transport ions in one direction only. For example, in the small intestine fluid and electrolytes secreted by crypt epithelial cells are absorbed by villous epithelial cells. Similarly, in exocrine glands fluid and electrolytes are secreted by acinar cells and absorbed by duct-lining epithelial cells. Thus, fluid is secreted into confined compartments (crypts, tubules and acini), rather than onto open surfaces, to facilitate the accumulation of solutes, which is crucial for iso-osmotic fluid flow (Sackin & Boulpaep, 1975).In this issue of the Journal of Physiology Shamsuddin and Quinton challenge the concept that individual airway surface epithelial cells oscillate between absorptive and secretory states. The authors’ex vivo bioelectric measurements on small airways from pig lungs acquired with a newly designed capillary Ussing chamber provide strong evidence for concurrent and constitutive absorption and secretion in this lung compartment. Secretion likely originates from pleats in the epithelium lining the small airways, whereas absorption is confined to epithelial folds that run axially down the airway lumen (see Fig. 7 of Shamsuddin & Quinton, 2012). It is suggested that the opening and closing of pleats during inhalation and exhalation, force secreted fluid out of the pleats and over the folds. Normal ASL volumes are maintained autonomously provided the fluid absorptive capacity of the folds exceeds the secretory rate of the pleats.The fluid recirculation model of Shamsuddin and Quinton is supported by three principal observations:The small (∼2 mV) transepithelial potential (Vt) in isotonic NaCl solutions, despite high selectivity for Cl− over Na+ (3:1). These data suggest that secretion by pleats shunts the Vt of the Na+ absorbing folds by recirculating Na+ via a paracellular pathway.The effects of Cl− channel inhibitors on Vt. Consistent with blockade of a secretory Cl− channel, the Ca2+-activated Cl− channel (CaCC) inhibitor niflumic acid hyperpolarised the apical membrane, and hence depolarised Vt. By contrast, the CFTR inhibitor GlyH-101 hyperpolarised Vt, reminiscent of its effects in absorptive sweat ducts. Taken together, these data suggest that CaCC mediates Cl− secretion by pleats concurrent with CFTR-driven Cl− absorption by folds.The disparate responses of Vt to Ca2+ and cAMP agonists. The Ca2+ mobilising purinergic agonist UTP hyperpolarised Vt, whereas the cAMP agonist forskolin depolarised Vt. The simplest interpretation of these data is that there are opposite driving forces for Cl− transport mediated by separate anion conductances. This suggests that different cell types permit simultaneous CaCC-mediated Cl− secretion and CFTR-driven Cl− absorption.The Shamsuddin and Quinton study is a major technical achievement, allowing for the first time bioelectric measurements in very small pieces (<1 mm2) of airway epithelium. It exposes an inherent weakness in bidirectional models of ion transport by airway epithelia: the necessity for acute and concerted changes in the activity of multiple channels and transporters as well as the ion selectivity of the paracellular pathway during the transition from absorption to secretion and vice versa. The model might also explain why cough clearance of the airways, associated with mechanical release of ATP and purinergic activation of CaCCs, is effective even in CF patients. However, the Shamsuddin and Quinton study is not without its limitations. First, the capillary Ussing chamber does not measure fluid transport or ASL height. Second, the potential contribution of electroneutral ion transporters (e.g. the Na+–H+ exchanger isoform 3 (NHE3); expressed in mouse airways; H. de Jonge, unpublished observation) to net fluid transport is unknown using the capillary Ussing chamber. Third, of necessity Shamsuddin and Quinton used pharmacological tools to dissect epithelial ion transport. As the authors acknowledge, these agents can have off-target effects.We foresee challenging experiments to test the fluid recirculation model of Shamsuddin and Quinton. For example, the localisation, by immunocytochemistry, of the Na+,K+,2Cl− cotransporter and CaCCs, such as TMEM16A, to small airway pleats. (Note that Wang et al. (2005) have already localised CFTR to the apical membrane of folds in pig small airways.) To confirm cell-specific differences in ion transport mechanisms and eliminate complications of paracellular shunting, intracellular microelectrodes and the patch-clamp technique might be used to investigate epithelial cells from the pleats and folds of small airways. A particularly intriguing question is the molecular mechanism(s) by which both CaCC and CFTR are constitutively active in pig small airways. Finally, it will be important to demonstrate that the fluid recirculation model is applicable to human small airways. Such additional studies will demonstrate convincingly whether fluid absorption and secretion in the small airways is compartmentalised and thus resembles the recirculation model of other epithelial tissues, in particular, the intestine. We anticipate that studies using pig models of CF (e.g. Ostedgaard et al. 2011) will provide an important test of the model of Shamsuddin and Quinton. We can't wait to see the data." @default.
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• W2117164023 date "2012-07-27" @default.
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• W2117164023 title "The small airways accordion: concurrent or alternating fluid absorption and secretion?" @default.
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• W2117164023 doi "https://doi.org/10.1113/jphysiol.2012.239657" @default.
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