Abstract
In upper airways airway surface liquid (ASL) depth and clearance rates are both increased by fluid secretion. Secretion is opposed by fluid absorption, mainly via the epithelial sodium channel, ENaC. In static systems, increased fluid depth activates ENaC and decreased depth inhibits it, suggesting that secretion indirectly activates ENaC to reduce ASL depth. We propose an alternate mechanism in which cholinergic input, which causes copious airway gland secretion, also inhibits ENaC-mediated absorption. The conjoint action accelerates clearance, and the increased transport of mucus out of the airways restores ASL depth while cleansing the airways. We were intrigued by early reports of cholinergic inhibition of absorption by airways in some species. To reinvestigate this phenomenon, we studied inward short-circuit currents (Isc) in tracheal mucosa from human, sheep, pig, ferret, and rabbit and in two types of cultured cells. Basal Isc was inhibited 20–70% by the ENaC inhibitor, benzamil. Long-lasting inhibition of ENaC-dependent Isc was also produced by basolateral carbachol in all preparations except rabbit and the H441 cell line. Atropine inhibition produced a slow recovery or prevented inhibition if added before carbachol. The mechanism for inhibition was not determined and is most likely multi-factorial. However, its physiological significance is expected to be increased mucus clearance rates in cholinergically stimulated airways.
Highlights
In human airways, mucociliary and cough clearance are critical components of mucosal innate defense[1,2]
inward short-circuit currents (Isc) was measured across excised tracheal epithelia of 5 species: humans, sheep, pigs, ferrets, and rabbits
Isc was measured across planer sheets of cultured primary human bronchial epithelia (HBE) and H441 human small airway cells
Summary
Mucociliary and cough clearance are critical components of mucosal innate defense[1,2]. A fundamental question in airway physiology is how airways orchestrate these opposing forces This question has mainly been explored in cultured surface epithelia, where it has been shown that cells respond to changes in the fluid volume covering them, resulting in a homeostatically controlled depth[4,5]. Na+ absorption by at least some airway surface epithelia is affected by ACh. Al-Bazzaz and colleagues[9,10], showed a biphasic response to basolateral carbachol in sheep bronchioles. Al-Bazzaz and colleagues[9,10], showed a biphasic response to basolateral carbachol in sheep bronchioles They observed an initial transient Isc increase followed by a long-lasting decrease due to inhibition of Na+ transport. A biphasic Isc response with corresponding increases and decreases in conductance was still observed after permeabilizing the apical membrane with amphotericin and imposing a K+ gradient, suggesting that ACh was transiently activating and inhibiting basolateral K+ channels under these conditions
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