The Proceedings of the American Thoracic Society 1:42-46 (2004)
© 2004 The American Thoracic Society
Regulation of Airway Surface Liquid Volume and Mucus Transport by Active Ion Transport
Robert Tarran
The University of North Carolina, Chapel Hill, North Carolina
Correspondence and requests for reprints should be addressed to Robert Tarran, Ph.D., Thurston-Bowles Building, The University of North Carolina, Chapel Hill, NC 27599–7248. E-mail: tarran{at}med.unc.edu
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ABSTRACT
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Mucus clearance is an important component of the lung's innate defense against disease, and the ability of the airways to clear mucus is strongly dependent on the volume of liquid on airway surfaces. Whether airway surface liquid (ASL) volume is maintained by passive surface forces or by active ion transport is controversial yet crucial to the understanding of how this system operates in both health and disease. In support of active ion transport being the major determinant of ASL volume, we have demonstrated that normal airway epithelia sense and autoregulate ASL height (volume) by adjusting the rates of Na+ absorption and Cl- secretion to maintain mucus transport.
Key Words: airway • cystic fibrosis transmembrane regulator • cystic fibrosis • chloride • mucus
Airway surface liquid (ASL) possesses a mucus component that traps inhaled particles; and a sol layer (periciliary liquid layer [PCL]) that keeps mucus at an optimum distance from the underlying epithelia, thus affecting the clearance of mucus (1–5). In normal airways, the PCL approximates the length of the outstretched cilia (approximately 7 µm), whereas the mucus layer varies considerably in height (7 to 70 µm in vivo) (6–8). The ASL also contains antibacterial agents (e.g., lysozyme and lactoferrin), migratory cells (i.e., neutrophils and macrophages), signaling molecules such as purines, and cytokines and ecto-enzymes (1). Thus, the ASL is a tightly regulated liquid layer that plays a major role in protecting the lung against infection.
The underlying airway surface epithelia have a low transepithelial resistance (9) and are highly water permeable (10–12); as a result, large transepithelial osmotic gradients cannot be maintained. This feature may initially appear disadvantageous for vectoral ion/water transport because extra energy must be expended to move ions/water against a continual backflux. However, leaky epithelia are capable of both absorbing Na+ and secreting Cl- (13), which may permit fine tuning of the ASL volume to effect efficient mucus clearance, as originally suggested by Kilburn in 1968 (14). Because ASL (NaCl) remains isotonic with plasma, it is important to consider the mass of NaCl in the ASL rather than the NaCl concentration as being the determining factor in influencing volume/composition. For example, if NaCl is secreted into the ASL by the epithelium, water will follow passively, causing the ASL volume to increase rapidly until isotonicity is achieved. Conversely, if NaCl is absorbed, water also follows passively in the opposite direction, causing ASL volume to decrease. Parenthetically, current models of leaky epithelia do not predict whether absorption and secretion occur simultaneously or concurrently and await further experimental evidence (15).
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THE RELATIONSHIP BETWEEN ASL HYDRATION AND MUCUS TRANSPORT
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Because of the importance of mucus clearance in airway defense, we investigated factors capable of altering mucus transport. The rate of mucociliary clearance is dependent on the rate of ciliary beating (16). However, it is also strongly influenced by the hydration state of the ASL/mucus (4, 17, 18). Mucus hydration is set by the volume of liquid present on airway surfaces, which in turn may be modified by active ion transport (discussed later here) (17). For example, adult patients with pseudohypoaldosteronism have downregulated rates of Na+ transport, and consequently, an abundance of ASL that results in clearance rates greater than those seen in normal control subjects (18). Unlike cystic fibrosis patients, who lack ASL volume (1), it seems that too much ASL does not compromise lung defense, and pseudohypoaldosteronism patients are infection-free in adulthood (18). To change mucus hydration in vitro, we indirectly altered the ASL volume of well differentiated bronchial surface epithelial cultures by varying serosal osmolalities and then measured changes in the height of the mucus layer by XZ-confocal microscopy (17). This protocol led to direct changes in the height of the mucus layer (Figure 1A), which shrank or swelled after anisotonic media changes. Despite these changes in height, the mucus layer remained in contact with the cilia and continued to be transported (Figure 1B). Transport was fastest when mucus heights were greatest and slowest when mucus height decreased. In a parallel set of experiments, we directly removed mucus from cultures after similar anisotonic serosal media changes and measured the wet–dry ratios to obtain percentage solids, as an index of the mucus concentration (Figure 1C). The percentage solids content increased or decreased in the presence of hypertonic or hypotonic serosal solutions, respectively, confirming that the liquid content of the mucus paralleled changes in mucus height and velocity. There was an inverse correlation between the mucus percentage solids content and mucus rotational velocity, with rotational velocity decreasing as mucus became concentrated. These studies thus emphasized the importance of hydration in influencing mucus velocity (Figure 1C).
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Figure 1. The relationship between mucus hydration and transportability. (A) Representative XZ-confocal images of airway surface liquid (ASL) (red) and green fluorescent microspheres (which associate discontinuously with mucus) after anisotonic media changes in the serosal bath. Serosal bath conditions: hypotonic (200 mOsm), isotonic (300 mOsm), and hypertonic (600 mOsm). Scale bar is 10 µm. (B) Photographs of rotational mucus transport after serosal media changes, as indicated by 5-second exposure streaks of microsphere movements. (C) Red axis = mean data from B (n = 5). Blue axis = percentage solids obtained from wet–dry ratios of mucus samples from airway cultures after anisotonic serosal media changes (n = 5–8). Data are shown as mean ± SEM.
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Active ion transport was also capable of modifying mucus hydration. Normal cultures doubled the percentage solids content within 72 hours to 6% by active Na+ absorption (19), which was accompanied by a reduction in ASL height and a slowing of mucus velocity (17).
These data suggest that water/ions may move between mucus and PCL to buffer PCL volume and keep the mucus layer at a suitable distance from the cilia to enable efficient mucus transport (17). This reservoir effect occurs without interruption in the discrete nature of the two layers and is likely achieved by mucins, which despite their low concentration (less than 2%) give mucus its characteristic visco-elastic and gel-forming properties (20). In vivo, a similar effect has been achieved by adding hypertonic saline to the airways. This results in a transient increase in mucus clearance, which is enhanced by amiloride addition, which blocks Na+ uptake through the epithelial Na+ channel (ENaC) (21).
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EVIDENCE FOR REGULATION OF ASL VOLUME IN AIRWAY SURFACE EPITHELIA
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Despite a large body of evidence demonstrating that airway epithelia actively transport ions and are water permeable [reviewed by Boucher (9)], it has been proposed that passive surface forces and not active ion transport are the primary regulators of ASL volume/composition (6, 22, 23). Potential examples of passive surface forces in the ASL include hydrostatic pressure between cilia, Donnan equilibria, and unidentified nonionic osmoles (23). It has been suggested that as ASL height approaches ciliary height, passive forces build up and counteract active ion transport to prevent further ASL absorption (23, 25). However, we have failed to find experimental evidence of such passive forces (17, 26) and, despite this lack of evidence, the primary mode of regulation of ASL height in normal airway epithelia remains controversial (1, 22, 24).
One possible approach to distinguish between these two models for ASL regulation is to examine the relationship between ASL height and the rate of active ion transport. For example, if ASL height is regulated by passive surface forces, ASL height should be independent of active ion transport rates. Conversely, if active ion transport does set ASL height, then altering Na+ absorption or Cl- secretion should result in changes in ASL height. As a first step toward testing this hypothesis, we have found evidence that airway epithelia are capable of adjusting the depth of the ASL so that it is close to the height of the extended cilia (17) (Figures 2A and 2B). Interestingly, as ASL height approached ciliary height, the rate of Na+ absorption decreased (as measured by amiloride-sensitive Vt) (Figures 2C and 2D). At this time (48 hours), Cl- secretion (bumetanide-sensitive Vt) (Figure 2D) became dominant, suggesting that the airway epithelia could sense ASL volume and convert from an absorptive to a secretory phenotype as required (17).
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Figure 2. ASL absorption (height) and epithelial bioelectric properties with time. (A) Representative confocal images of ASL (red) 0, 12, and 48 hours after mucosal addition of 20 µL of phosphate-buffered saline. (B and C) Plots of ASL height and transepithelial electric potential difference (Vt), respectively, over 48 hours (n = 8). (D) Bar graph depicting percentage changes in amiloride- and bumetanide-sensitive Vt immediately before phosphate-buffered saline volume addition and 48 hours afterward. *Data are significantly different (p < 0.05) from t = 0. Data are shown as mean ± SEM.
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NUCLEOTIDE RELEASE/METABOLISM AS A POTENTIAL REGULATOR OF ACTIVE ION TRANSPORT
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We are currently unaware of the mechanisms whereby normal airway epithelia signal changes in ASL volume and modify active ion transport rates. However, one possible signaling molecule is ATP, which is released by airway epithelia after diverse stimuli, including shear forces and increases in intracellular calcium (27). In vitro, cultured airway epithelia continually release purines and increase their rate of ATP release whenever the mucosal media is disturbed (28). In vivo, airway epithelia undergo mechanical stretch as the thoracic cavity expands during respiration and experience shear forces as air moves biphasically over the epithelia. These forces likely act as physiologic stimuli for ATP release.
The cystic fibrosis transmembrane regulator (CFTR) Cl- may be stimulated in an autocrine/paracrine fashion by adenosine (ADO) formed in the ASL from the metabolism of ATP, ADP, and AMP by ecto-nucleotidases and ecto-apyrases (Figure 3A). These ecto-enzymes are either located in the apical membrane of the superficial epithelia (28–30) or secreted into the ASL along with glandular secretions (31). Based on patch clamp data, Huang and colleagues (32) proposed that the coupling of luminal ADO receptors (A2b-R) to CFTR is compartmentalized in discrete apical domains and that the necessary proteins for this cascade are functionally very close to each other. They also noted that any changes in cAMP occurred close to the apical membrane and did not affect global cAMP levels. Further evidence for the intimacy of proteins involved in the A2b pathway has been provided by Matsuoka and colleagues (33), who coexpressed the A2b-R and CFTR in Xenopus oocytes and found that added ATP was metabolized to ADO by endogenous Xenopus ecto-nucleotidases, which then stimulated the A2b-R to activate CFTR. Surprisingly, CFTR was still active in the presence of high levels (1 U/ml) of ADO deaminase (which degrades ADO), and CFTR activation was only prevented when much higher concentrations of ADO deaminase were employed, again suggesting that the necessary components of the A2b system operate in their own microenvironment. This proximity has hampered measurements of the median effective concentration (EC50) of the A2b-Rs, which have been reported to vary from approximately 0.1–100 µM, depending on the system tested (34).
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Figure 3. Potential regulators of active ion transport. (A) Cellular ATP is secreted in response to diverse stimuli. Ecto-nucleotidases (and other enzymes) (eNT) then degrade ATP to adenosine (ADO), which activates A2b receptors (A2b-R) coupled to G proteins (Gs) and adenylyl cyclase (AC) to raise local concentrations of intracellular cAMP. cAMPi activates protein kinase A, which by phosphorylation activates cystic fibrosis transmembrane regulator (CFTR) and inactivates the epithelial Na+ channel (ENaC). (B) Cellular ATP autocrinally stimulates purinergic receptors (P2Y2-R), which are coupled to Gs and phospholipase C (PLC). PLC then increases inositol triphosphate (IP3) and Ca2+. The rise in intracellular Ca2+ (Ca2+i) then activates Cl- channels, and ENaC is indirectly inactivated via depletion of phosphatidylinositol 4,5-bisphosphate (PIP2).
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A complex interrelationship appears to exist between CFTR and ENaC. CFTR is positively regulated by ADO/cAMP and ENaC negatively regulated (Figure 3A) (35, 36). ENaC inhibition may be a mechanism to facilitate Cl- secretion against its chemical gradient because ASL (Cl-) is threefold to fourfold higher in ASL than intracellularly (9, 17). This lack of a chemical gradient for Cl- secretion can be circumvented by inactivation of ENaC, which hyperpolarizes the apical membrane, providing the necessary electrical driving force for cellular Cl- exit into the ASL (9).
Nucleotide addition has previously been demonstrated to increase mucus clearance in vivo (37). In addition to stimulating ciliary beating, Ca-activated Cl- channels are also activated to increase ASL secretions. ATP- and uridine 5'-triphosphate–mediated stimulation of apical P2Y2 receptors are coupled to G proteins and activate phospholipase C to increase inositol triphosphate and intracellular Ca2+ (27, 38) (Figure 3B). As with ADO and A2b-R, the lability of ATP has made the determination of EC50s for the P2Y2 subclass of purinergic receptors (P2Y2-R) difficult, and EC50 estimates have ranged from 0.2 to 1.0 µM (39–41).
We have recently established that mucosal nucleotide addition to airway epithelia induces ASL secretion onto airway epithelial surfaces (19) and also serves to increase mucus hydration/transport rates (19). However, the effects are relatively short lived, and ASL height returns to baseline values within 1 hour (19), consistent with Ussing chamber measurements of Ca2+-mediated anion secretion (42, 43). This short duration may in part be explained by the rapid ecto-metabolism (approximately 30 seconds) of even very large doses of ATP (> 200 µM) (19) and may also be due to internalization of the P2Y2-R or transience of the inositol triphosphate/Ca2+ signal (27, 39). This metabolism may thus provide normal airway epithelia with two different modes of Cl- secretion: sustained (via CFTR) and transient (via Cl- channels) (44). As with CFTR-mediated Cl- secretion, Cl- secretion through Cl- channels requires hyperpolarization of the apical membrane, which may be achieved via P2Y2-R–mediated activation inhibition of ENaC, possibly by depletion of phosphatidylinositol 4,5-bisphosphate (45).
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"THIN-FILM PHYSIOLOGY": A NEW PARADIGM FOR AIRWAY EPITHELIA?
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The majority of the literature pertaining to airway ion transport has been based on experiments performed with large volumes of Ringer/saline bathing epithelial mucosal surfaces. Under these conditions, ASL is grossly diluted and may even be washed away entirely. Thus, potential signaling molecules that could be secreted into the ASL are lost, which likely alters active ion transport rates. We believe future experiments will demonstrate ATP/ADO levels to be important regulators of active ion transport and mucus transport in superficial airway epithelia under "thin-film" conditions with native ASL.
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ACKNOWLEDGMENTS
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The author thanks his colleagues R. C. Boucher, C. W. Davis, B. R. Grubb, P. Huang, E. R. Lazarowski, H. Matsui, M. Picher, and M. J. Stutts, who played an important part in this research.
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FOOTNOTES
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Supported by the National Institutes of Health and the North American Cystic Fibrosis Foundation.
(Received in original form June 19, 2003; accepted in final form October 14, 2003)
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ABSTRACT
THE RELATIONSHIP BETWEEN ASL...
