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EDITORIAL FOCUS

Pulmonary Na⁺ transport induced by lung edema fluid

Lung Membrane Transport Group, Division of Maternal and Child Health Sciences, University of Dundee, Dundee, Scotland, United Kingdom

THE EPITHELIAL CELLS that line both the conductive airways and gas-exchanging regions of the lung actively absorb water from the overlying film of surface liquid, a process that is driven by electrogenic Na⁺ transport. The capacity to absorb water develops during the very last stages of gestation (3), enabling the perinatal removal of fetal lung liquid. This process is essential for the efficient establishment of air breathing, and its failure in premature infants contributes to the development of respiratory distress syndrome (RDS) in the newborn (12). It is clear that the lung's capacity to absorb Na⁺ is retained throughout adult life and is tightly regulated to prevent liquid accumulation in the gas-exchanging regions of the lung (15). However, in patients with pulmonary edema, the volume of liquid entering the air spaces may overwhelm this absorptive capacity. Although this life-threatening condition has many possible causes, including congestive heart failure, acute injury, and septic or hemorrhagic shock, its eventual resolution is dependent on lung epithelial Na⁺ absorption (11, 15).

Pulmonary Na⁺ transport thus plays an important role in protecting lung function, and this process is dependent, at least in part, on the expression of epithelial Na⁺ channels (ENaC). These transport proteins are composed of three subunits (-, -, and -ENaC) that together form a highly selective Na⁺ channel (4). In newborn mice, deletion of -ENaC disrupts the physiological perinatal absorption of lung liquid and causes death within 48 h of birth (8). Moreover, although heterologous expression of a rat -ENaC transgene can rescue this lethal phenotype, functional studies of these chimeric animals have shown that the respiratory epithelia display an abnormally low rate of Na⁺ transport and that in vivo, the mice are abnormally sensitive to experimentally induced pulmonary edema (5). These and other studies (10) thus suggest that ENaC is an important determinant of pulmonary Na⁺ transport throughout life. However, it is equally clear that amiloride, a drug that blocks ENaC at concentrations below 1 µM, does not entirely abolish Na⁺ transport in the adult lung (14). Despite much work, the channels underlying this amiloride-insensitive Na⁺ absorption have yet to be identified, and their role in pulmonary Na⁺ transport is only now beginning to be understood.

A series of three papers from Hugh O'Brodovich's group in Toronto, one of which is an article in focus in this issue (6), has given unexpected insights into the process of Na⁺ transport in pulmonary edema. The first of these papers (13) showed that edema fluid harvested from the lungs of adult rats with experimentally induced heart failure contained a factor, or factors, that almost doubled the rate of Na⁺ transport when applied to adult distal lung epithelial cells in monolayer culture. This fluid also hyperpolarized the transepithelial potential difference in explanted fetal mouse trachea, and, since this hyperpolarization persisted in the presence of bumetanide, the observation provided evidence that edema fluid could stimulate Na⁺ absorption. Further support for this interpretation came from studies of lung tissues explanted from fetal mice. It is well established that such explants normally expand into fluid-filled cysts when maintained in primary culture and that this expansion reflects the active secretion of liquid into the explant lumen (2). However, when treated with edema fluid, the explants displayed a net reduction in volume, indicating that the fluid had induced an absorptive phenotype.

Perhaps the most surprising outcome of these studies of Rafii and colleagues (13) was that this stimulatory effect of edema fluid was resistant to amiloride, suggesting that it was not dependent on ENaC. Further evidence supporting this conclusion came from the observation that the absorptive effect of edema fluid on fetal distal lung cysts persisted in tissues removed from -ENaC knockout mice. Although -ENaC is clearly important for the clearance of liquid from the neonatal lung (8), these results appear to show that edema fluid can induce an absorptive phenotype independently of this channel subunit. The identity of the cation channel involved in this response was not determined, but cyclic nucleotide-gated cation channels do not appear to be involved since inhibitors of these channels, which have also been implicated in lung liquid clearance (9), have only a very weak effect on the response to edema fluid.

In the second of the papers examining the effect of edema fluid on pulmonary Na⁺ and fluid transport, Elias and colleagues (6) have shed new light on the mechanisms underlying the response to edema fluid by making direct measurements of fluid transport across fetal distal lung epithelial cells in monolayer culture. Although the response to edema fluid was not absolutely identical to that described in the earlier study, these experiments clearly confirm that: 1) at high concentrations (i.e., undiluted), pulmonary edema fluid stimulates fluid absorption that persists in the presence of a concentration of amiloride that would be expected to completely block ENaC and 2) the net absorption of liquid from the lumen induced by edema fluid persists in tissues removed from -ENaC knockout mice. However, the most intriguing result to emerge from this study is that the transition from net secretion to net absorption induced by edema fluid is substantially reduced in fetal lung tissues isolated from both - and -ENaC knockout mice. It therefore appears that the absorptive response to edema fluid is dependent on these channel subunits but independent of -ENaC.

This result is surprising since it is widely accepted that the -subunit is the only subunit able to form a Na⁺-permeable channel in isolation and that the role of - and/or -ENaC is to modify the magnitude and conductive properties of this -ENaC-dependent conductance (4). It is therefore interesting that while - and -ENaC knockout mice can clear fluid from their lungs during the perinatal period, although at an abnormally low rate, the most severe consequence of deleting these genes is a profound dysfunction of renal ion transport (1). These new data, in contrast, indicate that - and -ENaC are both involved in the absorptive response to pulmonary edema and therefore suggest that these subunits might, in some unknown way, contribute to amiloride-resistant Na⁺ transport.

In the most recent paper in the series, Gandhi et al. (7), using primary cultures of rat alveolar type II (ATII) cells and in situ (lung slice) and in vivo experimental models, provide additional evidence that edema fluid stimulates Na⁺ transport in the adult lung, and, furthermore, that a factor responsible for the amiloride-insensitive component of the response resides in the globulin fraction of cardiogenic edema fluid. Since plasma from rats with congestive heart failure did not alter Na⁺ transport in cultured ATII cells, it is assumed that activation of the responsible factor(s) occurs during transudation from the circulation or within the air spaces. If the signaling pathways underlying the Na⁺ transport response to edema fluid can be determined, then this may open up new and potentially important therapeutic avenues to treat pulmonary disorders characterized by fluid accumulation in the newborn and adult lung, as in newborn and adult RDS.

	FOOTNOTES

 

Address for reprint requests and other correspondence: R. E. Olver, Division of Maternal and Child Health Sciences, Univ. of Dundee, Dundee DD1 9SY, Scotland, United Kingdom (e-mail: r.e.olver{at}dundee.ac.uk)

	REFERENCES

TOP REFERENCES

 

1. Barker PM, Olver RE. Clearance of lung fluid during the perinatal period. J Appl Physiol 93: 1542–1548, 2002.[Abstract/Free Full Text]
2. Blaisdell CJ, Morales MM, Andrade ACO, Bamford P, Wasicko M, Welling P. Inhibition of CLC-2 chloride channel expression interrupts expansion of fetal lung cysts. Am J Physiol Lung Cell Mol Physiol 286: L420–L426, 2004.[Abstract/Free Full Text]
3. Brown MJ, Olver RE, Ramsden CA, Strang LB, Walters DV. Effects of adrenaline and of spontaneous labour on the secretion and absorption of lung liquid in the fetal lamb. J Physiol Lond 344: 137–152, 1983.[Abstract/Free Full Text]
4. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC. Amiloride-sensitive epithelial Na⁺ channel is made of three homologous subunits. Nature 367: 463–466, 1994.[CrossRef][Medline]
5. Egli M, Duplain H, Lepori M, Cook S, Nicod P, Hummler E, Satori C, Scherrer U. Defective respiratory amiloride sensitive sodium transport predisposes to pulmonary oedema and delays its resolution in mice. J Physiol Lond 560: 857–865, 2004.[Abstract/Free Full Text]
6. Elias N, Rafii B, Rahman M, Otulakowski G, Cutz E, O'Brodovich H. The role of -, -, and -ENaC subunits in distal lung epithelial fluid absorption induced by pulmonary edema fluid. Am J Physiol Lung Cell Mol Physiol (May 18, 2007). doi:10.1152/ajplung.00373.2007.
7. Gandhi SG, Rafii B, Harris MS, Garces A, Mahuran D, Chen XJ, Bao HF, Jain L, Eaton DC, Otulakowski G, O'Brodovich HM. Effects of cardiogenic edema fluid on ion and fluid transport in the adult lung. Am J Physiol Lung Cell Mol Physiol (June 8, 2007). doi:10.1152/ ajplung.00464.2006.
8. Hummler E, Baker P, Gatzy J, Berrmann F, Verdumo C, Schmidt A, Boucher R, Rossier RC. Early death due to defective neonatal lung liquid clearance in -ENaC-deficient mice. Nat Genet 12: 325–328, 1996.[CrossRef][Web of Science][Medline]
9. Kemp PJ, Kim KJ, Borok Z, Crandall ED. Re-evaluating the Na⁺ conductance of adult rat alveolar type II pneumocytes: evidence for the involvement of cGMP-activated cation channels. J Physiol 536: 693–701, 2001.[Abstract/Free Full Text]
10. Li T, Folkesson HG. RNA interference for -ENaC inhibits rat lung fluid absorption in vivo. Am J Physiol Lung Cell Mol Physiol 290: L649–L660, 2006.[Abstract/Free Full Text]
11. Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of pulmonary edema in man. Am Rev Respir Dis 142: 1250–1257, 1990.[Web of Science][Medline]
12. Olver RE, Walters DV, Wilson SM. Developmental regulation of lung liquid transport. Annu Rev Physiol 66: 77–101, 2004.[CrossRef][Web of Science][Medline]
13. Rafii B, Gillie DJ, Sulowski C, Hannam V, Cheung T, Otulakowski G, Barker PM, O'Brodovich H. Pulmonary oedema fluid induces non-ENaC dependent Na⁺ transport and fluid absorption in distal lung. J Physiol Lond 544: 537–548, 2002.[Abstract/Free Full Text]
14. Ramsden CA, Markiewicz M, Walters DV, Gabella G, Parker KA, Barker PM, Neil HL. Liquid flow across the epithelium of the artificially perfused lung of fetal and postnatal sheep. J Physiol Lond 448: 579–597, 1992.[Abstract/Free Full Text]
15. Ware LB, Matthay MA. Alveolar epithelial fluid clearance is impaired in the majority of patients with acute lung injury and acute respiratory distress syndrome. Am J Respir Crit Care Med 163: 1376–1383, 2001.[Abstract/Free Full Text]

This Article Full Text (PDF) All Versions of this Article: 293/3/L535    most recent 00241.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Olver, R. E. Articles by Wilson, S. M. Search for Related Content PubMed PubMed Citation Articles by Olver, R. E. Articles by Wilson, S. M.