The role of Cl− in the regulation of ion and liquid transport in the intact alveolus during β‐adrenergic stimulation

Abstract

New findings What is the central question of this study?The co‐ordinated regulation of ion transport across the pulmonary epithelium determines the volume of the thin liquid layer lining the normal lung. However, the integrated homeostasis of the liquid transport physiology of the intact alveolus remains elusive. What is the main finding and its importance?Using a whole‐lung preparation, we explored the mechanism of the β‐agonist‐mediated upregulation of Na+ and alveolar liquid clearance, leading to resolution of pulmonary oedema. We demonstated the functional presence of secretory rather than absorptive Cl− channels, which implies that this upregulation is mediated via a direct effect on Na+ conductance and not through transepithelial Cl− absorption and an increased driving force for Na+. The epithelium of the developing lung displays an evolving liquid transport phenotype, in which Cl− secretion during fetal life is rapidly switched to Na+ absorption perinatally. However, the mechanisms underlying the homeostasis of the thin layer of liquid lining the postnatal pulmonary epithelium remain elusive. In particular, it remains unclear whether the stimulated clearance of excess alveolar liquid is mediated via transepithelial Cl− transport. Our study is a pharmacological analysis with the aim of addressing this issue, which is of major physiological significance in cases of pulmonary oedema from any cause. We measured the rate of transepithelial liquid movement (Jv) with 125I‐albumin, in the in situ perfused adult rat lung. Transepithelial Cl− transport was studied with the use of the Cl− channel inhibitor NPPB in the resting state and during stimulation with the β2‐adrenergic agonist terbutaline. The study of Jv in these conditions revealed the following findings: (1) there is net absorption of excess of alveolar liquid in the resting, unstimulated state, which is predominantly amiloride sensitive; (2) inhibition of Cl− transport with NPPB in the resting state results in a 1.6‐fold increase in net absorption of alveolar liquid; and (3) the terbutaline‐stimulated net absorption of the excess liquid is enhanced by 2.8‐fold in the presence of NPPB. Our results are suggestive of the functional presence of secretory, but not absorptive, Cl− mechanisms and show that transepithelial Cl− transport is not part of the mechanism underlying lung liquid clearance in response to β‐adrenergic stimulation.