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Epithelial Fluid Transport—A Century of Investigation

Kenneth R. Spring

K. R. Spring is Chief, Section on Transport Physiology, Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892–1603, USA.

	Abstract

 
Our current understanding of the mechanism of fluid transport by epithelia relies upon mathematical models developed 30 years ago to explain the mechanism of solute-solvent coupling and the pathways taken by water across an epithelium. The validity of these models is reconsidered in light of recent findings, and it is concluded that a simple three-compartment model system is adequate to explain fluid absorption and secretion by epithelia.

	Introduction

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 
The numbers have always been impressive–-180 liters of fluid absorbed across the human proximal renal tubule each day, 9 liters/day absorbed across the small intestinal epithelium–-although there is still a lack of consensus about the mechanism. A century ago, E. Waymouth Reid (6) correctly concluded that the absorption of fluid across isolated intestine required an intact epithelium and that fluid transport occurred when the bathing media on both sides of the tissue were identical in composition (see Ref. 8). In the subsequent 100 years, over 1,500 scientific papers have been published on the topics of fluid absorption and secretion by epithelia. How far we have come in our understanding and what remains to be explained is the substance of this review.

The modern era of investigation of fluid transport began some 40 years ago when Curran and Solomon (2) demonstrated the relationship between the NaCl content of the lumen of isolated rat small intestine and the rate of volume flow out of the lumen. They perfused the intestinal lumen with isosmotic solutions with various NaCl concentrations and measured the rate of fluid absorption. They showed that the luminal fluid remained isosmotic as fluid was absorbed and that the rate of fluid absorption was proportional to the rate of solute absorption, even when the NaCl concentration was reduced well below normal plasma levels. Thus transepithelial solute absorption was shown to be the primary event and the principal determinant of the transepithelial water flux. Similar studies by Windhager et al. (12) in the proximal tubule of Necturus kidney demonstrated that the volume flow across the tubule was a linear function of the transepithelial NaCl flux and that this flux was dependent on metabolism. At that point, the bulk of the research effort on fluid-transporting epithelia was directed toward elucidating the site and mechanism of the coupling between the solute and water fluxes.

The first model that explained vectorial fluid transport in the absence of external osmotic gradients was put forth by Curran and MacIntosh (1). As shown in Fig. 1, solute transport into the middle compartment resulted in fluid movement from the outer to the inner compartment. The membrane separating the middle and outer compartments was semipermeable and similar to a cell membrane. The membrane separating the middle and inner compartments was freely permeable to both solutes and water, resembling the basement membrane and interstitial connective tissue. When solute was injected into the middle compartment, water was drawn into this compartment from the outer bath by osmosis across the outer-facing membrane. Osmosis could not occur across the inner membrane because of the low solute reflection of this membrane. As water entered the middle compartment the pressure within it rose and forced fluid across the leaky inner membrane. The pressure caused flow of both solute and water across the inner membrane because of its high permeability compared to that of the outer membrane.

View larger version (13K): [in this window] [in a new window]   FIGURE 1. Curran and MacIntosh (1) 3-compartment model for coupling of solute and water transport in epithelia. The outer-facing membrane is semipermeable (high water permeability and relatively low solute permeability); the inner-facing membrane is nonselective (high water and solute permeabilities). Solute that enters the middle compartment by active transport from the adjacent cells draws water by osmosis across the outer membrane. Water movement into the middle compartment increases the hydrostatic pressure and drives solutes and water across the inner-facing membrane, resulting in vectorial transport from the outer to the inner bath.

	The standing-gradient model revisited

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 
In brief, the model depicts the LIS as an asymmetric compartment into which solute is transported preferentially into the blind end (sealed by the tight junction) with a resultant local increase in osmolality (i.e., the standing gradient). The increased osmolality of the LIS draws water from the adjacent cells, thereby increasing the hydrostatic pressure in the LIS, distending the spaces, diluting the fluid, and forcing the fluid out of the channel mouth and into the underlying interstitial space. Mixing within the LIS is assumed to be poor because of restrictions to diffusion caused by tortuosity or molecular hindrance. Although significant osmotic forces are not exerted across the basal opening of the LIS because of the low reflection coefficient of the basement membrane and connective tissues, oncotic forces can substantially aid in fluid absorption (10).

In the intervening years, virtually all of these key components of the standing-gradient model have been shown to be incorrect: solute pumps were not clustered at the blind end of the LIS but were uniformly distributed; the tight junctions were remarkably leaky to transported solutes; the cell membrane water permeabilities used in the model were shown to be gross underestimates because of unstirred layer artifacts and methodological limitations; the diffusion of small solutes in the LIS was not restricted (9, 13). Thus we are presently faced with the dilemma of interpreting and understanding fluid absorption and secretion by epithelia while virtually nothing remains to support our framework for such interpretation. Although many alternative models have been generated over the last two decades, they have failed to displace the standing-gradient model. Recent results from my own laboratory and those of colleagues lend additional support to the conclusion that a simple, three-compartment model, similar to that first proposed by Curran, is adequate to explain fluid transport by epithelia. In this context I will consider two major unresolved issues: Is the transport of water osmotically driven? What is the route taken by water across a fluid-transporting epithelium?

	Is water transport due to osmosis?

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 
The movement of water may be treated theoretically in the same manner as the flow of any substance: water is driven by the gradient in its electrochemical potential. The primary driving forces for water movement are the relative concentrations of water across a barrier (i.e., the osmolality difference) and the hydrostatic pressure difference. It was central to the early models that solute transport into the LIS or cell interior would result in osmosis in direct proportion to the water permeabilities of the relevant cell membranes. Indeed, when the water permeabilities of epithelial cell membranes were measured they were found to be sufficiently high that transepithelial transport could be accounted for by very small osmolality differences (3–30 mosmol/kg).

Recently, it has been proposed that fluid transport is not the result of osmosis, but instead is a consequence of "molecular water pumping" caused by microscale pinocytosis (5). This concept is a variant of one that was suggested and quickly rejected more than 35 years ago. The old scheme required endocytotic vesicular uptake of fluid at one membrane (e.g., the apical cell membrane), translocation of the vesicles to the opposite membrane (e.g., the lateral or basal membrane), and subsequent exocytosis. The scheme was rejected on two grounds–-first, the number of vesicles required was impossibly large; second, there could be little or no solute selectivity. The problem of the sheer number of vesicles is best illustrated by a calculation for the rat proximal tubule where the fluid absorption rate is such that the entire cell volume is transported every minute. The volume of a rat proximal tubule cell is ~800 x 10^-15 liters, whereas that of a 0.1-µm-diameter vesicle is ~5 x 10^-19 liters. Therefore, 160,000 vesicles would be required to be endocytosed and exocytosed across each cell every minute.

In the recent proposal, the impediment of the requisite huge number of vesicles is avoided by postulating that the transported water molecules are those engulfed when the conformational change occurs in the active site of a cotransporter (e.g., for Na-coupled glucose transport, ~210 water molecules/1 glucose). Even if such a conformational change could result in vectorial water transport, an unproven speculation at this time, the problem of the required number of transporters remains. To accomplish the observed rate of transepithelial transport in the rat proximal tubule of 800 x 10^-15 l/min of water (equivalent to 265 x 10¹¹ water molecules), ~10¹¹ glucose molecules need to be transported across the apical membrane each minute. If the maximum turnover rate of the glucose transporter is 100/s, ~1.7 x 10⁷ transporters are needed in the apical membrane of each cell, equivalent to a transporter density of ~3 x 10⁵/µm² of apical membrane. Furthermore, the exit of water from the cell is hypothesized to occur by a similar cotransporter-dependent mechanism at the basolateral membrane, necessitating a similar number of transporters to be active in those membranes. The required number of cotransporters in either membrane far exceeds reasonable estimates for any epithelial cell, rendering the hypothesis very unlikely.

The potential contribution of cotransported water to fluid absorption in the proximal tubule may be calculated in another way using classical clearance equations. If 210 water molecules are cotransported with each glucose and all the glucose is reabsorbed in the proximal tubule, the maximum percentage of the glomerular filtrate that could be reabsorbed by this mechanism is 1.9%, determined from the relative concentrations of glucose (5 mM) and water (55.5 M) in the filtrate. Taking all possible cotransported species into account still could only account for <5% of the absorption by the proximal tubule.

In summary, further consideration of the alternatives to osmotically driven fluid transport seems fruitless and a potential distraction from efforts directed toward greater understanding of the sites and mechanism of coupling of solute and water movements in epithelia.

	Route of water flow

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 
For 30 years, a lively debate has continued about the partition of water flows across an epithelial layer. The discovery of substantial ionic permeability of tight junctions opened the door for speculation about significant water fluxes through the paracellular pathway (9). The appeal of this route of water flow was that cell integrity would not be compromised by the relatively large volume of transported fluid. Numerous studies using indirect methods pointed toward a substantial paracellular component of the water flux, up to 50%, in the rat proximal tubule (9, 10). Recently, two studies concluded that paracellular water flow across leaky epithelia was far smaller.

In the first study, the velocity and magnitude of the fluid flow in the LIS of Madin-Darby canine kidney cells grown on permeable supports were determined by confocal fluorescence microscopy (4). It was concluded that the flow velocity at the tight junction was indistinguishable from zero unless the junctional permeability was greatly increased by the stimulation of protein kinase A. Even when the permeability was so increased, the fraction of transepithelial flow that was paracellular was minuscule. Related investigations showed that the diffusion of small solutes within the LIS was not restricted compared to that in free solution (13). Recall from our previous considerations that such a restriction was an essential component of the standing-osmotic gradient model, because solute concentration gradients were unlikely to develop along a LIS that allowed diffusion at free solution rates.

In the second study, fluid transport was studied in the renal proximal tubules from mice in which the aquaporin-1 (AQP-1) gene had been knocked out (7). AQP-1 conveys most of the water permeability to the apical membrane of proximal tubule cells. It, and other members of the aquaporin family, are present in virtually every fluid-transporting epithelium as well as in other highly water-permeable cells. The water permeability of the proximal tubule was decreased by ~80% in the knockout mice compared to controls, about what would be expected if the only remaining permeability was that associated with the cell membrane lipids. These results are incompatible with previous estimates of a large paracellular component for fluid transport across the proximal tubule and offer strong support for a wholly transcellular route for water.

The rate of fluid absorption at the end of the proximal tubule in the knockout mice was reduced to about one-half of that of controls. This absorption rate is somewhat less than that predicted from the water permeability reduction. It is likely that the transepithelial osmotic gradient generated by active transport was increased in the knockout mice as a compensatory mechanism, but measurements of the luminal osmolality were not done in this investigation. Even in the absence of such measurements, this study strongly supports the conclusion that fluid absorption by the mammalian proximal tubule is exclusively transcellular and driven by osmosis. Finally, it is worth noting that according to the "molecular water pump" hypothesis, the large reduction in cell membrane water permeability in proximal tubules of the knockout mice would be predicted to result in a large increase in the rate of fluid absorption rather than the observed substantial decrease.

	A new paradigm?––The Curran three-compartment model resurrected

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 
If one accepts the above conclusion, the model for an absorptive epithelium is simplified and virtually identical to that offered by Peter Curran in the early 1960s. Figure 2 shows such a simplified scheme. The basic sequence is as follows: solute enters the cell by passive downhill flow through channels (e.g., Na⁺), exchangers (e.g., Na⁺/H⁺, Cl^-/HCO₃^-), or by cotransport (e.g., Na⁺-K⁺-2 Cl^-, Na⁺-organic). Solute influx causes cell osmolality to increase slightly (and/or luminal osmolality to decrease) as indicated in the figure; water flows from lumen to cell at a rate determined by the osmotic gradient and the apical membrane water permeability. Water flows from the luminal rather than the basal solution into the cell because the basolateral interstitial space is slightly hypertonic to the cytoplasm (see Fig. 2). Solute transport, principally that by the Na⁺-K⁺-ATPase, is the engine that drives fluid transport and leads to solute accumulation in the LIS and basal infoldings with an increased osmolality in these regions. Water is then drawn from the cell interior to the LIS and basal infoldings by the small osmotic pressure difference across the basolateral cell membrane, a highly water-permeable membrane in absorptive epithelia. The resultant absorbate emerging from the mouth of the LIS and basolateral infoldings is slightly hypertonic to the luminal bath, in agreement with the few measurements of absorbate osmolality that have been reported (9). The basal interstitium constitutes a significant unstirred layer that both enables the accumulation of transported solute in the LIS and infoldings, even though the diffusion of small solutes is not significantly impeded within these regions, and acts as the site across which the transported solute concentration decreases to equal that of the basal bathing solution. In such a simplified scheme, LIS geometry and distensibility are not the critical determinants of absorbate osmolality that they were thought to be in the standing-gradient scheme. Accumulation of fluid within the LIS and basal infoldings should still increase the hydrostatic pressure in these compartments and could result in their distension, depending on the compliance of the cell membranes.

View larger version (37K): [in this window] [in a new window]   FIGURE 2 . An absorptive epithelium is shown schematically. Solute movements are shown with solid arrows and water movements with dashed arrows. Solute entry across the apical membrane occurs by diffusion through channels, cotransport, or exchange; solute exit across the basolateral membrane is shown as active transport mediated primarily by Na+-K+-ATPase. Approximately 15–20% of transported Na+ is shown leaking back into the lumen across the tight junction. Relative osmolalities indicated in each compartment are shown as percentages of bathing solution values. Water enters the cell across the apical membrane because of the small (2–4%) hyperosmolality of the cytoplasm and leaves across the basolateral membrane driven by a similarly small osmotic pressure difference (3–6%). Basement membrane and basal connective tissue constitutes an unstirred layer across which solutes and water diffuse, dissipating the increased solute concentration of the lateral intercellular spaces and basal infoldings. Uptake into subepithelial capillaries is not shown but would primarily result from oncotic, Starling forces. Graph, bottom, depicts osmolality profile expected for a cross section through the middle of an epithelial cell.

A good illustration of the second benefit of solute permeation across the tight junction is offered by anion absorption in the rat proximal tubule. Bicarbonate and organic solutes are preferentially absorbed in the first segment of the proximal tubule leading, in the second segment of the tubule, to slight electronegativity of the tubule lumen and a luminal Cl^- concentration exceeding that of the interstitium. Because the tight junctions in this segment are anion selective, Cl^- absorption is passive and predominantly paracellular, driven by favorable electrical and chemical gradients.

Thus a simple compartmental model allowing free diffusion of small solutes within the compartments is sufficient to account for absorptive fluxes of both solutes and water.

	Fluid secretion

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 
Can the process of fluid secretion be completely understood in a similarly simplified scheme? The present-day answer is yes, with reservations. Virtually all secretion occurs into the acinar lumen of glands. Most glandular structures have an acinus connected to a lumen lined with solute-absorbing cells. It is relatively easy to envision, but somewhat difficult to measure, that solute transport across the apical membrane of the acinar cells and into the lumen leads to a hyperosmotic acinar lumen. In principle, solute uptake at the basolateral membranes could also result in a modestly hypoosmotic interstitium adjacent to the cell; however, such hypotonicity has not been demonstrated experimentally. Clearly, if water is to move from the cell interior to the lumen, there must be favorable osmotic gradients directed across both the basolateral and apical cell membranes. Again, without direct experimental evidence, the alternative has been suggested that water secretion is paracellular, driven by the osmotic gradient across the tight junctions. By analogy to the recent results in absorptive epithelia, this seems an unlikely possibility. In glands, solute absorption along the more distal portions of the secretory duct may lead to a secretion that is isotonic or very hypotonic (e.g., saliva) or may vary in its osmolality depending on the action of hormones on the rate of ductal transport.

	Secretion across a flat epithelium—The problem of airway surface liquid

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 
Although the above scheme serves reasonably well for glandular secretion, conceptual problems arise when secretion by relatively flat, sheetlike epithelia is postulated. A salient example is the generation of airway surface liquid (ASL) in the lung and the involvement of the cystic fibrosis transmembrane conductance regulator (CFTR) in this process. On the initial discovery of the CFTR gene and the functional characterization of the protein, it was tacitly assumed that CFTR was involved in fluid secretion by virtue of its role as a Cl^- channel. Because one of the primary clinical manifestations of the disease is a thickening of the mucin-rich ASL and subsequent respiratory infections, attention was riveted on the role of a defective CFTR in anion secretion. Some subsequent investigations have failed to demonstrate secretion and have, in fact, offered strong support for a role for CFTR in anion absorption across the airways. Accompanying this uncertainty have been a confusing array of measurements of airway surface liquid composition and osmolality from normal and CFTR-deficient animals that have ranged from profoundly hypotonic to hypertonic values for the ASL. Clearly, the site and mechanism of ASL generation and subsequent solute transport must be identified and characterized before the etiology of the disease can be understood. This process is made more difficult by the fact that the ASL is a 10-µm-thick layer of solution, rich in mucus and bounded by an air-water interface. An isotonic primary secretion would tend to be dehydrated by exposure to inspired air creating a hypertonic ASL. Subsequent solute absorption by airway epithelial cells, possibly regulated by CFTR, may be an essential component of maintenance of ASL osmolality and thickness. It is indeed remarkable that our understanding of a major disease arising from a defect in the mechanism of ion transport and thence fluid transport is so hampered by the lack of an acceptable model for ASL generation and maintenance.

	Summary—A hundred years of progress?

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 
Both E. Waymouth Reid and Peter Curran developed a remarkably clear understanding of the mechanism of fluid transport by epithelia. Although we have added many refinements to their concepts, sometimes wandering afield, our knowledge of the crucial details still exhibits surprising gaps. Molecular methods combined with functional assays are opening the door to understanding the process of fluid transport, but the technical impediments imposed by epithelial geometry and permeabilities are considerable. We need to understand the fundamentals of fluid transport and to agree on universal principles to establish etiologies of the many disorders of this process that are seen in the clinic. The remarkable capacity of epithelia to absorb or secrete huge quantities of fluid, modify the secretion or absorption rates, and alter the composition of the transported fluid continues to amaze and confound us.

	Acknowledgments

 
I thank Dr. M. B. Burg for his insightful comments and criticisms and Drs. O. N. Kovbasnjuk and M. L. Barnard for critically reading the manuscript.

	References

Top Introduction The standing-gradient model... Is water transport due... Route of water flow A new paradigm?––The Curran... Fluid secretion Secretion across a flat... Summary—A hundred years of... References

 

1. Curran, P. F., and J. R. MacIntosh. A model system for biological water transport. Nature 193: 347–348, 1962.[Medline]
2. Curran, P. F., and A. K. Solomon. Ion and water fluxes in the ileum of rats. J. Gen. Physiol. 41: 143–168, 1957.[Abstract/Free Full Text]
3. Diamond, J. M., and W. H. Bossert. Standing-gradient osmotic flow. A mechanism for coupling of water and solute transport in epithelia. J. Gen. Physiol. 50: 2061–2083, 1967.[Abstract/Free Full Text]
4. Kovbasnjuk, O. N., J. P. Leader, A. M. Weinstein, and K. R. Spring. Water does not flow across the tight junctions of MDCK cell epithelium. Proc. Natl. Acad. Sci. USA 95: 6526–6530, 1998.[Abstract/Free Full Text]
5. Meinild, A.-K., D. A. Klaerke, D. D. F. Loo, E. M. Wright, and T. Zeuthen. The human Na⁺-glucose cotransporter is a molecular water pump. J. Physiol. (Lond.) 508: 15–21, 1998.[Abstract/Free Full Text]
6. Reid, E. W. Transport of fluid by certain epithelia. J. Physiol. (Lond.) 26: 436–444, 1901.
7. Schnermann, J., C.-L. Chou, T. Ma, T. Traynor, M. A. Knepper, and A. S. Verkman. Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice. Proc. Natl. Acad. Sci. USA 95: 9660–9664, 1998.[Abstract/Free Full Text]
8. Schultz, S. G. A century of (epithelial) transport physiology: from vitalism to molecular cloning. Am. J. Physiol. 274 (Cell Physiol. 43): C13–C23, 1998.[Abstract/Free Full Text]
9. Spring, K. R. Routes and mechanisms of fluid transport by epithelia. Annu. Rev. Physiol. 60:105–119, 1998.[Medline]
10. Weinstein, A. M., J. L. Stephenson, and K. R. Spring. The coupled transport of water. In: New Comprehensive Biochemistry. Membrane Transport, edited by S. L. Bonting and J. J. H. H. M. De Pont. Amsterdam: Elsevier, 1981, vol. 2, p. 311–351.
11. Whitlock, R. T., and H. O. Wheeler. Coupled transport of solute and water across rabbit gallbladder epithelium. J. Clin. Invest. 43: 2249–2265, 1964.
12. Windhager, E. E., G. Whittembury, D. E. Oken, H. J. Schatzmann, and A. K. Solomon. Single proximal tubules of Necturus kidney. III. Dependence of H₂O movement on NaCl concentration. Am. J. Physiol. 197: 313–318, 1959.
13. Xia, P., P. M. Bungay, C. C. Gibson, O. N. Kovbasnjuk, and K. R. Spring. Diffusion coefficients in the lateral intercellular spaces of MDCK cell epithelium determined with caged compounds. Biophys. J. 74: 3302–3312, 1998.[Medline]

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