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EDITORIAL FOCUS
Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, Ohio
REABSORPTION OF FETAL LUNG FLUID at birth and resolution of alveolar edema in the adult lung are driven by active sodium and chloride transport across the alveolar epithelial barrier (for review see Ref. 8). The rate of fetal lung fluid absorption and alveolar edema removal can be increased by both catecholamine-dependent and -independent mechanisms (5, 8, 9).
The review by O'Brodovich and colleagues (12) in this issue describes the involvement and importance of amiloride-insensitive Na+ absorption pathways in the distal lung. The potential importance of amiloride-insensitive Na+ absorption can be illustrated by the fact that these pathways seem to account for 20–80% of distal lung fluid absorption in different species (2, 3, 5, 6, 8–10, 12). Only 40–50% of distal lung fluid absorption is amiloride sensitive (15), and cAMP-dependent lung fluid absorption in the human lung may depend on cystic fibrosis transmembrane regulator activation (4). In this review (12), the authors propose that among candidate Na+ channels that could be responsible for the amiloride-insensitive portion of distal lung fluid absorption, a potential candidate would be an "A-typical ENaC" (A-ENaC) that may consist of subunits in a different stoichiometry than the traditional ENaC 2
-, 1β-, and 1
-subunit stoichiometry. Proposed stoichiometries of these A-ENaCs include - channels or an addition of a 
-subunit to form 2-1β-1-1 ENaC. A second candidate channel that might be responsible for the amiloride-insensitive portion of distal lung fluid absorption would be the cyclic nucleotide-gated (CNG) Na+ channel. Evidence of its involvement comes from in vivo rat studies and expression studies in rat lung and airways. In the in vivo rat studies, this class of Na+ channels was demonstrated to be involved in removing the fluid from the distal air spaces after β-adrenergic activation (11). mRNA for CNG channels have also been demonstrated along the respiratory tract (1, 16). A third candidate for the amiloride-insensitive fraction of distal lung fluid absorption may be the nonselective cation channel. It is abundantly expressed in the pulmonary epithelia but requires very high Ca2+ concentrations to become activated (13, 17). However, since it is blocked by intracellular adenosine nucleotides, like AMP, this channel seems like an unlikely candidate for the amiloride-insensitive component of distal lung fluid absorption.
The authors (12) also carried out experiments in which they administered inhibitors of amiloride-insensitive Na+ transport pathways to fetal distal lung epithelial cells and alveolar epithelial type II cells grown under both submersion and air-liquid interface conditions. These monolayers were mounted in Ussing chambers, and their bioelectric properties were measured. Addition of diltiazem, pimozide, and dichlorobenzamil had minimal effects on short-circuit current. These data indicate that, at least under baseline conditions, there were insufficient numbers of pimozide-, diltiazem-, or dichlorobenzamil-sensitive Na+ channels to affect the bioelectric properties of the intact monolayers. The results remain inconclusive but suggest that further in vivo research be directed to these Na+ channels as candidates for the elusive and potentially important amiloride-insensitive portion of distal lung fluid absorption in both newborn and adult lungs.
From this research (12), two conclusions can be made. First, amiloride-insensitive Na+ transport is an important mechanism for lung Na+ and fluid absorption. Second, although some inhibitor studies have suggested that amiloride-insensitive conductances and transepithelial Na+ transport can be identified, the definitive molecular and functional contribution to vectorial transport remains unknown. Accordingly, it is likely that significant progress on the mammalian lung's amiloride-insensitive Na+ and fluid absorption will not occur until a specific inhibitor is found together with novel approaches to identify what gene product is responsible.
The second article discussed in this editorial (14) studied the reduced expression of the β-subunit of the ENaC and its effects on distal lung fluid absorption in mice. To define a role of the β-ENaC subunit in vivo in the mature lung, these investigators (14) studied a previously established mouse strain harboring a disruption of the β-ENaC gene locus that resulted in low levels of β-ENaC mRNA expression. The most significant discovery from these studies was that the disappearance of β-ENaC from the lung epithelia resulted in a compensatory upregulation of -ENaC and -ENaC subunits. This effect in turn may have resulted in a formation of A-ENaC-like channels with various subunit stoichiometries. The low β-ENaC expression seemed to favor the expression of - ENaC with and without the -ENaC subunit attached to it. The resulting A-ENaC have a reduced sensitivity to amiloride inhibition and do not seem to respond to β-adrenergic stimulation with an increase in activity. In an earlier study by Li and Folkesson (7), disruption of the -ENaC subunit expression by specific small interfering RNA attenuated the responses to both terbutaline stimulation and amiloride inhibition in the rat lung. Thus, both of these results (7, 14) are important in light of the review by O'Brodovich and colleagues (12) regarding the influence of amiloride-insensitive Na+ transport pathways. The results from these studies (7, 14) suggest that variations in ENaC subunit expression with different resulting subunit stoichiometries may explain variabilities in rate and amiloride sensitivity of the Na+ and the rate of fluid absorption across the lung epithelium.
In summary, presence of all three ENaC subunits, -, β-, and -, seem to be essential to maintain basal distal lung fluid absorption with normal sensitivity to amiloride inhibition and β-adrenergic stimulation (7, 12, 14). Perturbations in expression of one or more of the subunits may lead to reduced baseline lung fluid absorption and attenuated amiloride sensitivity as well as a reduced stimulation by β-adrenergic agonists. Further investigations into these A-ENaC channels as well as into the expression and function of the CNG channels may improve our understanding of what mechanisms constitute the amiloride-insensitive portion of distal lung fluid absorption.
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FOOTNOTES |
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REFERENCES |
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 TOP REFERENCES |
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-ENaC inhibits rat lung fluid absorption in vivo. Am J Physiol Lung Cell Mol Physiol 290: L649–L660, 2006.This article has been cited by other articles:
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  C. S. Rogers, W. M. Abraham, K. A. Brogden, J. F. Engelhardt, J. T. Fisher, P. B. McCray Jr., G. McLennan, D. K. Meyerholz, E. Namati, L. S. Ostedgaard, et al. The porcine lung as a potential model for cystic fibrosis Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L240 - L263. [Abstract] [Full Text] [PDF]
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