Spectrum of ion channels in alveolar epithelial cells: implications for alveolar fluid balance
Paul J. Kemp1,2 and
Kwang-Jin Kim2
1School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom; and 2Department of Medicine and Will Rogers Institute Pulmonary Research Center, University of Southern California, Keck School of Medicine, Los Angeles, California 90033
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ABSTRACT
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The efficient transition from placental to atmospheric delivery of oxygen at birth is critically dependent on rapid reabsorption of fetal lung fluid. In the perinatal period, this process is driven by active transepithelial sodium transport and is almost exclusively dependent on expression and modulation of the amiloride-sensitive epithelial sodium channel (ENaC). However, later in development, the amiloride sensitivity of the reabsorptive response, which must be sustained to keep the lungs effectively dry, wanes as a function of postnatal age. This Featured Topic (Experimental Biology Meeting, Washington, DC, April, 2004) presented exciting new evidence to demonstrate that, in addition to ENaC, the adult alveolar epithelium expresses a plethora of amiloride-insensitive ion channels, including cystic fibrosis transmembrane conductance regulator, proton channels, voltage-dependent potassium channels, and cyclic nucleotide-gated cation channels. Furthermore, important evidence for selective modulation of ENaC subunits in the lung in response to cardiovascular disease was demonstrated. Finally, it is clear that newly emerging models of human alveolar epithelium in combination with the novel lung slice electrophysiological preparation will ensure that the ascription of function to specific ion channels in the in situ human lung will soon be a real possibility.
IT HAS LONG BEEN KNOWN that the switch from placental to pulmonary delivery of O2, which must occur to ensure the successful and smooth transition from in utero to terrestrial living, is critically dependent on a rapid and sustained reabsorption of lung liquid at birth. Pioneering work by Olver and colleagues (43) in the late 1980s, employing the chronically catheterized fetal lamb lung model, demonstrated clear evidence for an epinephrine-dependent lung fluid reabsorptive response that was mimicked by cAMP analogs (53) and was completely reversed upon luminal addition of the potassium-sparing pyrazine diuretic amiloride. Furthermore, this group demonstrated that quantitative development of this response was under tight ontological control of both thyroid and adrenal cortical hormones (4) as well as environmental factors such as PO2 (1, 45). These and later data from various models in several species (23, 41, 50) provided a good explanation of how fluid reabsorption might be initiated during labor by the huge surge in circulating fetal epinephrine and experimentally reinforced the notion that the most important component of the perinatal lung fluid reabsorptive response was amiloride sensitive. After the identification and molecular cloning of the
-,
-, and
-subunits of the epithelial sodium channel (ENaC) (10, 11) and the differential localization of these sodium channel subunits to the lung in general (11) and alveolar epithelial type II cells in particular (35), it became increasingly clear that active sodium transport, energized by a basolaterally positioned Na-K-ATPase, might be responsible for generating an osmotic driving force of magnitude sufficient to promote lung fluid reabsorption at birth after activation of apical ENaC by
-adrenergic receptors. Such a hypothesis was robustly and soundly tested in 1996 by Hummler and colleagues (22) who showed that transgenic mice lacking expression of functional
-ENaC were unable to clear their lungs of fluid and died within 2 days of birth. These mice demonstrated waterlogged lungs upon postmortem analysis.
Once the successful transition from lung liquid secretion to fluid reabsorption has been made at birth, so that gaseous exchange may continue optimally throughout postnatal life, the lung retains the capacity to absorb liquid, apparently without the need for any "classic" exogenous stimuli. Importantly, the cellular mechanisms responsible for generating the continued reabsorptive driving force during postnatal development appear to differ rather considerably from the exclusively amiloride-dependent processes that predominate in fetal life. Thus although resting fluid reabsorption in neonatal sheep (aged
14 days) can be completely abolished by amiloride (in fact, amiloride instillation into early neonatal lungs results in a return to the fetal, secretory phenotype), this pharmacological agent is a rather poor inhibitor of fluid reabsorption by the time the animals have reached 6 mo of age and the capacity for lung liquid secretion appears to have been irreversibly lost (27). These seminal observations of Junor and colleagues (27) suggested that the role of ENaC in lung fluid homeostasis later in development is less clear than it is for fetal and early neonates. Indeed, evidence is now emerging from studies in several species that further supports a significant role for amiloride-insensitive pathways in adult lung fluid reabsorption, including that of Norlin and colleagues (39, 40) who demonstrated that up to 70% of adult guinea pig and 55% of adult rat lung fluid reabsorption was amiloride insensitive. These observations, which have essentially been made in whole lung preparations, have resulted in two major new questions being posed by workers in the field as we attempt to understand lung fluid homeostasis (and its dysfunction in various lung pathologies) in the 21st century: 1) What is the molecular nature of the postnatal, amiloride-insensitive component of the fluid reabsorptive response and; 2) To which cellular component of alveolar epithelium (alveolar type I and/or alveolar type II cells) is each of the separate mechanisms localized?
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AMILORIDE-INSENSITIVE ION CHANNELS
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In the postnatal lamb lung preparation, the pharmacology of inhibition of lung fluid reabsorption is consistent with the involvement of cyclic nucleotide-gated cation channels (27), a notion supported recently by Norlin and colleagues (40) who have shown direct upregulation of amiloride-insensitive fluid reabsorption by cGMP; expression of this phenotype appears to be under developmental control since pimozide (a cyclic nucleotide-gated cation channel blocker) is ineffective in fetal lamb lung (26). Recently, these in vivo data have been corroborated in a cellular system by demonstrating amiloride-insensitive, cGMP-evoked whole cell sodium currents in postnatal rat alveolar epithelial cells sensitive to blockade by pimozide and di/trivalent cations, including Zn2+ (28). Clearly, together, these recent findings suggest the scenario that such cyclic nucleotide-gated cation channels are an important contributor to adult lung fluid homeostasis (perhaps both sodium absorption and potassium secretion). Intriguingly, the very recent data of Ehrhardt and colleagues (18) employing monolayers of human alveolar epithelial cells (see below) clearly show that, quantitatively, the most significant component of the short-circuit current is Zn2+ sensitive, suggesting that cyclic nucleotide-gated cation channels may be important in adult human alveolar epithelial ion and fluid handling.
In addition to the essential role of amiloride-sensitive and -insensitive sodium channels, there is overwhelming evidence for the functional expression of a number of other ion conductances. These include calcium-sensitive and -insensitive potassium channels (15, 29, 32, 42, 44), proton channels (see below and Refs. 13 and 14), and chloride channels, including cystic fibrosis transmembrane conductance regulator (CFTR) (see below and Refs. 9, 24, 30, 31, and 42). Although the possible role of these ion channels in alveolar fluid homeostasis has been reviewed by various researchers (34, 42), exact mechanistic information is still rather lacking. For example, active secretion of potassium has been alluded to in isolated perfused rat lung studies (5), but currently we cannot be sure which specific channel types are involved. It is of interest, however, that Leroy and colleagues (32) have recently reported the presence of ATP-sensitive potassium channels in the alveolar epithelium which may, in combination with voltage-dependent and calcium-sensitive potassium channels, contribute to transepithelial transport of sodium and chloride by maintaining the electrochemical driving force across the alveolar epithelium. Of further importance to alveolar homeostasis may be to understand how these ion channels are regulated by neurohumoral factors under pathophysiological conditions [e.g., acute respiratory distress syndrome and congestive heart failure (CHF)]. In this regard, some factor(s) in lung edema fluid have been reported to stimulate short-circuit current across rat distal lung epithelial cell monolayers (47). Similarly, the stimulatory role of proteinase for sodium absorption across lung epithelial barrier(s) has been a focus of intense research (17, 51). A particularly important area of interest in pathophysiology of the lung is CHF (46, 47, 49, 52), for which some exciting new information (see below) on regulation of ENaC has recently become available.
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SUMMARY OF NEW FINDINGS ON THE FUNCTIONS OF ALVEOLAR EPITHELIAL ION CHANNELS AND THEIR REGULATION
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Here we summarize important recent findings (presented at one of the Featured Topic sessions in the Experimental Biology Meeting, April, 2004, Washington, DC) that deal with function and regulation of several ion channels expressed in mammalian alveolar epithelial barrier. DeCoursey et al. (16) presented findings on alveolar epithelial proton channel properties. Voltage-gated proton channels can contribute to recovery from an acid load in A549 and rat type II cells (37), which may contribute to CO2 elimination by the lung (13). The unitary conductance of H+ channels determined in type II cells was not affected by changes in pH of the bathing fluid of the cells but increased approximately threefold when intracellular pH was decreased from 6.5 to 5.5, consistent with the notion that steady-state H+ current flows outward across the type II cell membrane. Extrapolating the conductance to physiological pH, the single-channel H+ current (at
50 mV positive to the Nernst potential) is roughly 1 fA, which is
1,000 times smaller than unitary potassium or sodium currents through most ion channels. The intriguing possibility that proton channels might be involved in regulation and/or maintenance of the acid-base status of the alveolar fluid is a subject for future investigation.
Bankir and Bouby (3) presented data on possible influence of vasopressin on lung fluid transport. These investigators previously found, using a number of rat models (including Wistar, Sprague-Dawley, Brattleboro, and salt-sensitive Sabra), that vasopressin increases mRNA abundance of
- and
-subunits of ENaC in the kidney and lung [an organ that also expresses vasopressin V2 receptors (V2R)] (38). Interestingly, after chronic (1 wk) alterations in vasopressin levels or water intake, extrarenal water losses (= water intake urine output) exhibited significant changes that paralleled those observed in urine output, a twofold increase in extrarenal water losses with administration of SR-121463, a selective V2R antagonist, and a 50% decrease in extrarenal water loss after infusion of 1-desamino-8-D-arginine vasopressin, a V2R agonist (2). Because extrarenal water loss occurs mainly in the respiratory system, these investigators assumed that vasopressin might influence fluid clearance in the respiratory system, probably via ENaC-dependent sodium transport. More detailed molecular analysis and in vitro functional studies are required for confirmation of V2R-dependent modulation of lung fluid clearance and involvement of ENaC.
Muellertz and colleagues (36) presented findings on a rat model of CHF. Three weeks after the induction of CHF (increased left ventricular end diastolic pressure accompanied by right ventricular hypertrophy and pulmonary congestion), the expression of
-ENaC was increased, whereas the expression of
-ENaC and aquaporin (AQP)-5 was decreased. Protein levels of the
-subunit of the Na-K-ATPase were unchanged. By contrast, after 30 wk,
-ENaC,
-ENaC,
-Na-K-ATPase, and AQP-5 were all downregulated. These observations prompted these investigators to argue that the alterations in expression pattern of ENaC subunits (i.e., a marked increase in the
-ENaC:
-ENaC ratio in CHF 3 wk after induction of CHF) might be indicative of a shift in the cationic channel properties from highly sodium-selective to nonselective phenotype, which could result in potentially less efficient sodium reabsorption across the alveolar epithelium. Furthermore, these investigators argued that the decreased expression of Na-K-ATPase and AQP-5 after 30 wk of induction of CHF is suggestive of longstanding heart failure being associated with decreased capacity for pulmonary fluid resolution. Further analyses of in vitro and in situ alveolar epithelial models generated from this CHF model (especially the long-term model) may be useful to address such premise(s) in the future.
Fang and colleagues (20) presented data on CFTR-mediated alveolar fluid clearance using an in vitro model of human primary alveolar epithelial type II cell monolayers. By day 5 in primary culture at an air interface, a confluent cell monolayer had formed with low protein permeability and electrical resistance of
1,800
·cm2. Immunostaining and electron microscopy demonstrated a typical type II cell phenotype, with lamellar bodies and microvilli. Basal fluid transport, measured by radiolabeled macromolecule concentration changes, was
0.9 µl·cm2·h1. Exposure of monolayers to forskolin increased the fluid transport to 1.5 µl·cm2·h1. CFTRinh-172, a specific CFTR inhibitor, had no effect on basal fluid transport but inhibited forskolin-stimulated fluid transport. Amiloride decreased transmonolayer current (due to an arbitrarily imposed NaCl concentration gradient) by
25%, whereas CFTRinh-172 reduced the transmonolayer current in the presence of forskolin stimulation (but not at baseline condition). In support of these functional studies, quantitative real-time PCR showed high mRNA levels of CFTR and surfactant protein C (i.e., a specific marker of alveolar type II cells). These investigators contended that CFTR is expressed in human alveolar type II cells and may play an important role in fluid transport in human alveolar epithelium during elevations in cAMP.
In addition to the identification of CFTR in human type II cell monolayers, a further contribution to the session was the observations of Ehrhardt and colleagues (18) pertaining to the cation conductance of human alveolar epithelium. Freshly isolated human type II cells grown under conventional culture conditions (i.e., liquid-covered culture) express a pattern of differentiation markers that are consistent with the hypothesis that in vitro transdifferentiation of primary cultured human type II cells to a type I cell-like phenotype had occurred on permeable supports (19, 21). Moreover, immunocytochemistry revealed expression of ENaC predominantly at the apical aspect and
2-adrenoceptors predominantly at the basolateral aspect of cultured cells. Ussing chamber studies showed that short-circuit current decreased to
13% at 5 min after application of 1 mM ouabain to the basolateral fluid, indicating the role of Na-K-ATPase in transepithelial active ion transport. Intriguingly, amiloride decreased short-circuit current by only
30%, whereas ZnCl2, an inhibitor of nonspecific cation channel activities, produced an
70% inhibition. Effects of both amiloride and ZnCl2 (applied to apical fluid) were additive, regardless of the order of application. After basolateral application of terbutaline, short-circuit current increased to
250% of control with a fast response time (<10 min). When applied to apical fluid, terbutaline stimulation demonstrated a long lag time, supporting the immunofluorescence microscopy data of predominant localization of
2-adrenoceptors at the basolateral aspect. These bioelectric properties are qualitatively similar to those found in rat alveolar epithelial cell monolayers, with some distinct differences. For example, sensitivity of human cells toward amiloride appears less than that found in rat model, and terbutaline was less effective when applied to apical fluid. Perhaps most interesting, however, is the predominance of Zn2+ sensitivity in human (consistent with expression of cyclic nucleotide-gated cation channels), as opposed to very little, if any, Zn2+ sensitivity in rat monolayer models (Kim, unpublished data). Clearly, more studies are required to address such species differences.
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CELLULAR LOCALIZATION OF ALVEOLAR TRANSPORT PROTEINS
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The second piece of crucial information currently missing from the picture that defines lung fluid homeostasis concerns the potential differential location of key ion channels and transport proteins within the alveolar epithelium itself, alveolar type I cells or alveolar type II cells? Thus, until very recently, the processes that underlie physiological fluid reabsorption were believed to be physically situated exclusively in the alveolar type II cell. Although it is true that alveolar type II cells express the entire gamut of proteins believed to be important for efficient vectorial ion, solute, and water transport, the potential contribution to the reabsorptive response of alveolar type I cells has only recently been made possible, due essentially to the difficulty in routinely isolating such cells. This problem has been confounded by the use of polarized monolayers of adult alveolar cells consistently reported as being type II cultures but that are, at best, a mixture of type I and type II cells (12, 33).
However, in the last 2 yr, a number of reports have been published showing that freshly isolated alveolar type I cells express proteins consistent with a role for this cell type in vectorial ion transport. Thus, employing immunohisto- and immunocytochemistry, two concurrent reports demonstrated expression of
-ENaC in both alveolar type I and type II cells (6, 25), whereas AQP-5 was demonstrated to be exclusively localized to the apical membrane of the alveolar type I cells (6). With the use of a relatively low-purity cell preparation, alveolar type I cells were put firmly on the functional map by the demonstration that they transported sodium in an amiloride-sensitive manner; quantitatively, this sodium transport was almost 2.5-fold larger than that afforded by alveolar type II cells (25). Further and direct evidence for the involvement of alveolar type I cells in fluid transport came from the exciting ex vivo observation that the ouabain sensitivity of the largest proportion of lung fluid reabsorption more closely matched that of the
2-subunit of the Na-K-ATPase (a subunit claimed to be localized exclusively to the type I cell) (48). Further investigations utilizing isolated type I cells (and confluent monolayers thereof) are required to confirm such an ex vivo observation at the cellular level.
Thus, although type I cells are now heavily implicated in alveolar ion transport, direct electrophysiological evidence of specific ion channels is completely lacking. There are two main reasons for such a gap in our knowledge. First, until very recently, highly pure alveolar type I monolayers had not been generated (making short-circuit current measurements unfeasible). Second, isolated alveolar type I cells appear to be overly fragile and, as a consequence, have been unamenable to patch-clamp studies. The first problem may not be insurmountable, especially with the very recent data showing relatively pure (>90%) alveolar type I monolayer production for the first time (albeit bioelectric properties and active ion transport data on type I monolayer model are lacking) (12). With regard to electrophysiological study, it has been shown very recently that viable, 200- to 300-µm lung slices can be cut from postnatal rat and mouse lungs that can be differentially immunostained using antibodies specific for extracellular epitopes localized exclusively for alveolar type I or type II cells (8). Furthermore, cells that have been positively identified within the lung slice are then amenable to patch clamp in situ and subsequent robust, single-channel characterization (7). This exciting new development has allowed, for the first time in lung, the identification of a number of ion channels, including those selectively permeable to cations.
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CONCLUSION
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Over the last three decades, evidence has slowly accumulated demonstrating that finely regulated fluid transport across the alveolar epithelium is physiologically important to the transition from intra- to extrauterine life and to maintenance of an optimal environment for air breathing thereafter. Central to this fluid transport is the expression of numerous ion channels. To understand fully how these ion channels act coordinately to generate an osmotic driving force of sufficient magnitude to keep the lung lumen dry, numerous tissue and cellular preparations have been probed with a variety of different techniques. However, the present challenge is to understand more completely the mechanisms involved in lung fluid homeostasis by seeking answers to the important questions: Which channels are expressed?, Where they are localized within the alveolar epithelium?, and What role do they play in alveolar fluid clearance in health and disease? The recent development of a pure type I cell preparation (that may form tight monolayers), together with in situ lung slice electrophysiology, may provide new insights into the mechanisms of ion transport in the lung. However, such insight can only be useful when fully integrated with knowledge gleaned from intact animal studies and, ultimately, with the new human models of lung ion and fluid transport now beginning to emerge.
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GRANTS
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The authors thank the following agencies for continued support: National Heart, Lung, and Blood Institute (Grants HL-38658 and HL-64365), Wellcome Trust, British Heart Foundation, and Hastings Foundation.
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ACKNOWLEDGMENTS
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This paper is in part based on the synopsis of presentations and discussions that took place at the Featured Topic session on spectrum of alveolar epithelial ion channels, Experimental Biology 2004 Meeting, Washington, DC, April, 2004. The authors appreciate the excellent presentations of their findings by the speakers (Drs. L. Bankir, T. DeCoursey, C. Ehrhardt, J. Fang, and K. Muellertz) and lively discussions from the participants at the Featured Topic session.
Present address of P. J. Kemp: Cardiff School of Biosciences, Cardiff University, Biomedical Sciences Bldg., Museum Ave., PO Box 911, Cardiff CF10 3US, Wales, UK (E-mail: KempPJ{at}Cardiff.ac.uk).
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FOOTNOTES
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Address for reprint requests and other correspondence: P. J. Kemp, Cardiff School of Biosciences, Cardiff University, Biomedical Sciences Bldg., Museum Ave., PO Box 911, Cardiff CF10 3US, Wales, UK (E-mail: KempPJ{at}Cardiff.ac.uk)
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