Alveolar epithelial ion and fluid transport: recent progress.

Studies of epithelial ion and fluid transport across the distal pulmonary epithelia have provided important new concepts regarding the resolution of pulmonary edema, specifically the removal of edema from the distal airspaces of the lung. Overall, there is convincing evidence that vectorial ion transport across the alveolar and distal airway epithelia is the primary determinant of alveolar fluid clearance (AFC). The general paradigm is that active Na and Cl transport drives net alveolar fluid clearance, as demonstrated in several different species, including the human lung. The objective of this article is to consider some areas of recent progress in the field of alveolar fluid transport under normal and pathologic conditions. More detailed reviews of this field including studies of the immature and the newborn lung are available (1–10). In the lung, as in other epithelia, ion transporters and other membrane proteins are asymmetrically distributed on opposing cell surfaces, conferring vectorial transport properties to the polarized epithelial cells (Figure 1). There are epithelial cells in the distal airway epithelia, such as Clara cells, that are capable of vectorial ion transport. The vast majority of the surface area available for transport in the distal lung is occupied by the alveolar epithelial type I (ATI) and type II cells (ATII). Tight junctions populate these epithelial cells near their apical surfaces, thereby sustaining apical and basolateral cell polarity (11). The permeability of tight junctions is dynamic and regulated, in part, by cytoskeletal proteins and intracellular Ca concentrations and possibly by ion channels (11). Figure 1. A section of an ARDS lung. Note the fluid-filled alveolar spaces with significant red blood cell infiltration. Insert demonstrates apical ENaC staining and basolateral Na,K-ATPase staining in lung epithelia. (Reprinted with permission from Ref. 3) Because ATII cells can be isolated from the lung and studied in vitro, they have been studied extensively. ATII cells are responsible for surfactant secretion (12) as well as vectorial Na and Cl transport. Na uptake occurs on the apical surface, partly through amiloride-sensitive and amiloride-insensitive channels. Subsequently, Na is pumped actively from the basolateral surface into the lung interstitium by the Na,K-ATPase. An epithelial Na channel (ENaC) participating in Na movement across the apical cell membrane has been cloned and well characterized (13, 14). Recent evidence indicates that the CFTR is expressed in ATII cells and plays a role in cAMP-mediated fluid transport (15–18). The role of ATI cells for AFC is less known, although several studies have established a possible contribution of ATI cells to vectorial fluid transport (19–22). ATI cells express aquaporin 5 (23), Na,K-ATPase (21), and ENaC (21, 22). The presence of Na,K-ATPase is consistent with a role for ATI cells in AFC, but is not conclusive since Na,K-ATPases are needed to maintain cell volume. However, one study using pharmacologic methods to inhibit the α2-subunit of the Na,K-ATPase suggested a role for Na,K-ATPase in driving fluid clearance across type I cells in vivo (24). Another study reported a role for the α2-Na,K-ATPase under cAMP-stimulated conditions, suggesting that type I cells may be involved, as the α2-subunit seems to be expressed only in type I cells (25). Detailed studies of type I cells have been limited to date because of difficulty maintaining them in cell culture although recent work has demonstrated functional ion channels in freshly isolated ATI cells with electrophysiologic evidence for Na channels (ENaC), K channels, and CFTR Cl channels (26). In addition, there is evidence for ENaC expression (21, 22) and a partial amiloride inhibition of 22Na-uptake in freshly isolated rat ATI cells (22). Evidence for β-adrenoceptor (βAR) expression in ATI cells has also been reported (20, 27). In addition, ATI cells may be involved in macromolecular transport due to the presence of vesicles and caveolin (28). The distal airway epithelium also actively transports Na (29–31).