Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema

Abstract

Alveolar fluid clearance driven by active epithelial Na + and secondary Cl − absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na + channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl − secretion and alveolar Cl − influx were quantified by radionuclide tracing and alveolar Cl − imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl − secretion and alveolar Cl − influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na + -K + -Cl − cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR −/− mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl − secretion that were again CFTR-, NKCC-, and Na + -K + -ATPase-dependent. Our findings show a reversal of transepithelial Cl − and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl − and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema.epithelial Cl − transport | pulmonary edema T raditionally, the formation of cardiogenic pulmonary edema has been attributed to passive fluid filtration across an intact alveolocapillary barrier along an increased hydrostatic pressure gradient. However, recent studies show that cardiogenic edema is critically regulated by active signaling processes. Activation of mechanosensitive endothelial ion channels increases lung vascular permeability (1), whereas alveolar epithelial cells lose their physiological ability to clear the distal airspaces from excess fluid by their capacity to actively transport ions across the epithelial barrier (2-4).In the intact lung, the predominant force driving alveolar fluid clearance is an active transepithelial Na + transport from the alveolar into the interstitial space. A major portion of the apical Na + entry is mediated by the amiloride-inhibitable epithelial Na + channel (ENaC), with basolateral Na + extrusion through the Na + -K + -ATPase (5). Cl − and water are considered to follow paracellularly for electroneutrality and osmotic balance. In cardiogenic lung edema, the physiological protection against alveolar flooding provided by an intact alveolar fluid clearance is largely attenuated (3, 4). Previously, ...

Chloride secretion across adult alveolar epithelial cells contributes to cardiogenic edema

“…However, Wolk et al (11) showed that alveolar instillation of a CFTR inhibitor decreased alveolar fluid clearance (AFC) by about 20%, suggesting the presence of transcellular Cl − movement through the CFTR. Solymosi et al (8) also report that inhibitors of the CFTR decreased AFC by 25-30%. Previously, Fang et al (12) showed that ΔF508 mice, the most common CFTR mutation, had normal levels of Na + -dependent AFC, but in contrast to wild-type mice, did not increase their AFC following instillation of β-agonists or forskolin.…”

“…It is possible that in mice with congestive heart failure, decreased endothelial NO synthase activity and NO levels may be an important compensatory mechanism, limiting the extent of lung edema formation. Thus, the study by Solymosi et al (8) clearly enhances our understanding of the mechanisms leading to the formation of pulmonary edema following an acute increase in left atria pressure and elucidates an important unique mechanism for the therapeutic potential of furosemide.…”

“…Previous studies (9,10) documented that an acute increase of pulmonary or left atrial pressures decreased active Na + reabsorption across the alveolar epithelium, which contributed to pulmonary edema. Thus, the study by Solymosi et al (8) offers fresh insight into the mechanism of edema formation following an acute increase of left atrial pressure. In contrast to the fetal fluid, which is essential to lung development, accumulation of alveolar fluid in the adult lung compromises gas exchange.…”

“…In PNAS, Solymosi et al (8) show that an acute increase of left atrial pressure in isolated perfused rat lungs decreases amiloridesensitive Na + reabsorption across alveolar epithelial cells and stimulates Na + and Cl − uptake through the basolateral NKCC transporter. Decreased Na + entry through ENaC in epithelial cells also resulted in hyperpolarization of their apical membranes, providing the driving force for Cl − secretion and fluid accumulation in the alveolar spaces.…”

“…In addition, when Na + transport is compromised and a favorable Cl − gradient is established, Cl − secretion may occur. In PNAS, Solymosi et al (8). (Fig.…”