Abstract
A balance sheet describing the integrated homeostasis of secretion, absorption, and surface movement of liquids on pulmonary surfaces has remained elusive. It remains unclear whether the alveolus exhibits an intra-alveolar ion/liquid transport physiology or whether it secretes ions/liquid that may communicate with airway surfaces. Studies employing isolated human alveolar type II (AT2) cells were utilized to investigate this question. Human AT2 cells exhibited both epithelial Na(+) channel-mediated Na(+) absorption and cystic fibrosis transmembrane conductance regulator-mediated Cl(-) secretion, both significantly regulated by extracellular nucleotides. In addition, we observed in normal AT2 cells an absence of cystic fibrosis transmembrane conductance regulator regulation of epithelial Na(+) channel activity and an absence of expression/activity of reported calcium-activated chloride channels (TMEM16A, Bestrophin-1, ClC2, and SLC26A9), both features strikingly different from normal airway epithelial cells. Measurements of alveolar surface liquid volume revealed that normal AT2 cells: 1) achieved an extracellular nucleotide concentration-dependent steady state alveolar surface liquid height of ∼4 μm in vitro; 2) absorbed liquid when the lumen was flooded; and 3) secreted liquid when treated with UTP or forskolin or subjected to cyclic compressive stresses mimicking tidal breathing. Collectively, our studies suggest that human AT2 cells in vitro have the capacity to absorb or secrete liquid in response to local alveolar conditions.
Highlights
The alveolar surface consists of two main cell types, alveolar type I (AT1)2 and alveolar type II (AT2) cells
Naϩ uptake occurs at the apical surface of rat AT2 cells in large part through the amiloride-sensitive epithelial Naϩ channel (ENaC) [7,8,9], and in situ hybridization studies have identified the presence of mRNA for all three subunits of ENaC in rat alveolar cells [8, 9]
Evidence for alveolar liquid secretion was demonstrated by confocal microscopy in mice, which was blunted by the CFTR inhibitor (CFTRinh-172) and was absent in CFTR(Ϫ/Ϫ) mice, suggesting that the murine alveolar epithelium secrete liquid via CFTR
Summary
The alveolar surface consists of two main cell types, alveolar type I (AT1)2 and alveolar type II (AT2) cells. We studied the integrated functions of ion transport via measuring the volume of the AvSL produced by cultured normal human AT2 cells under basal and stimulated conditions with confocal microscopy. The change in Ieq in response to CFTRinh172 was small, ϳ0.4 A/cm2, suggesting that normal AT2 cells exhibit only a small rate of CFTR-mediated ClϪ secretion under study were performed on AT2 cultures 4 –9 days after seeding.
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