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. 2011 Apr 26;589(Pt 12):2935–2943. doi: 10.1113/jphysiol.2011.208298

Lymphatic fluid: exchange mechanisms and regulation

Virginia H Huxley 1, Joshua Scallan 2
PMCID: PMC3139077  PMID: 21521763

Abstract

Abstract

Regulation of fluid and material movement between the vascular space of microvessels penetrating functioning organs and the cells therein has been studied extensively. Unanswered questions as to the regulatory mechanisms and routes remain. Significantly less is known about the lymphatic vascular system given the difficulties in seeing, no less isolating, these vessels lying deeper in these same tissues. It has become evident that the exchange microvasculature is not simply a passive biophysical barrier separating the vascular and interstitial compartments but a dynamic, multicellular structure subject to acute regulation and chronic adaptation to stimuli including inflammation, sepsis, diabetes, injury, hypoxia and exercise. Similarly lymphatic vessels range, in their simplest form, from lymphatic endothelium attached to the interstitial matrix, to endothelia and phasic lymphatic smooth muscle that act as Starling resistors. Recent work has demonstrated that among the microvascular lymphatic elements, the collecting lymphatics have barrier properties similar to venules, and thus participate in exchange. As with venules, vasoactive agents can alter both the permeability and contractile properties thereby setting up previously unanticipated gradients in the tissue space and providing potential targets for the pharmacological prevention and/or resolution of oedema.

Virginia H. Huxley is the JO Davis Professor of Cardiovascular Physiology and Director of the National Center for Gender Physiology at the University of Missouri-Columbia School of Medicine. Her research focuses on the mechanisms regulating microvascular water and solute transport in health and disease. Joshua Scallan performed his graduate work on this topic at the University of Missouri-Columbia. He applied his background in cardiovascular physiology to studying the permeability of lymphatic endothelium to water and solute, which, until now, remained unexplored. He is currently a Postdoctoral Fellow at St. Jude Children's Research Hospital in Memphis, TN, USA.

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Introduction

It is well known that the blood capillary network serves to supply all of the tissues in the body with nutrients, water, oxygen and signalling proteins, as well as to remove waste and transport immune cells. Less well understood and more difficult to study is the lymphatic vasculature lying in the tissue nearby. Demonstrating its importance is that in the absence of lymphatic function, life ceases and when it is dysregulated, pathology ensues. Water and the particles dissolved in it, referred to as solute, move between the blood and the tissue. Their direction of movement is influenced both by hydrostatic and oncotic (hence protein concentration) pressure differences across the vessel wall and by the actively regulated permeability of the vessel wall. While much has been elucidated concerning the mechanisms governing solute and water transport by and across the blood vasculature, whether or not these same mechanisms operate in the lymphatic vasculature remains an unexplored territory. Here we review briefly what is known concerning the regulation of blood microvascular exchange and then relate that to developing research on the regulation of lymphatic exchange and its contribution to tissue homeostasis.

Blood vascular forces influencing fluid homeostasis

At the blood–tissue interface of microvessels, the balance of hydrostatic (ΔP) and oncotic (Δπ) pressures determines the direction of water and solute movement between the blood and tissue spaces. This statement forms the basis of Starling's Law of fluid filtration (Starling, 1896). In equation form, fluid flux (Jv, cm3 s−1) across a surface S (cm2), with hydraulic permeability Lp (cm s−1 cmH2O−1), is Jv=LpS(ΔP–σΔπ) where σ is a unitless coefficient accounting for how well the blood–tissue interface acts as a perfect semi-permeable membrane. Usually, these forces are slightly out of balance such that water and solute are filtered from the blood into the tissue; i.e. the pressures in the vascular space exceed that of the tissue, with the difference in vascular hydrostatic pressure dominating (Levick & Michel, 2010). However, as written, an implication of Starling's Law of Fluid Filtration is that fluid reabsorption is possible when the gradient in oncotic pressure exceeds that of the hydrostatic pressures (σΔπ > ΔP). Solute movement is similar in that its movement is a product of diffusive and convective mechanisms. Fick's First Law states that solute will move (Js, mmol s−1) across a surface (S) of permeability (Pd, cm s−1) when concentration differences exist (ΔC). Again the direction of movement is determined by ΔC and it is to be noted that it is ΔC that determines the magnitude of Δπ, as (π=ϕnC, where ϕ is a unitless coefficient and n the valency number). Solutes, particularly those that are of larger size and lower kinetic energy, can also be pulled across the wall into the tissue by water by the hydrostatic pressure-dependent process of convection or solvent drag (Michel & Phillips, 1987).

In reality there are more determinants of fluid filtration than just hydrostatic and oncotic pressures. The available surface area for exchange is an important factor at both the single vessel level and the network level. Intuitively, less fluid can be filtered across a microvessel of smaller radius or shorter length because there is less surface area for exchange in contact with the fluid. Likewise, when fewer capillaries are perfused in a given network, the cumulative fluid filtration is reduced. Other important factors to be considered are the permeability coefficients Lp and Pd themselves in addition to processes that alter barrier structure and transport mechanisms that can elevate or diminish flux directly. All of the factors influencing fluid movement also influence solute movement and vice versa (Scallan et al. 2010). More importantly, all of these factors are actively regulated by the microvasculature – resulting in either raising or lowering of the permeability – to maintain fluid homeostasis.

Regulation of vascular forces that determine fluid balance

Hydrostatic pressure is maintained by the arterioles, the smallest vessels on the arterial side of the vasculature. Arterioles respond to changes in pressure and/or flow via their myogenic response (Davis & Hill, 1999). For example, when pressure or flow drops, the smooth muscle layer of these vessels sense a reduction in stretch with changes in vessel diameter and respond by relaxing to maintain the initial vessel diameter, thus flow and pressure. As a consequence the downstream capillary beds experience almost constant pressure under conditions of normal physiology. In the pathophysiological situation of capillary hypertension, however, these vessels will experience increases in pressure that can dramatically increase fluid filtration into the interstitium (Scallan et al. 2010). The network surface area can be regulated dynamically through capillary recruitment and is determined chiefly by upstream arteriolar tone. In chronic states in response to exercise or hypertension, for example, the architecture of the network can be modified permanently (Humar et al. 2009) through new vessel growth (angiogenesis) to increase surface area or vessel pruning/remodelling (rarefaction) to reduce exchange surface area.

Both Lp and Ps (apparent permeability to solute, cm s−1) can be regulated actively by the vascular endothelium in response to circulating vasoactive peptides, hormones, metabolites and numerous other signalling molecules (see Mehta & Malik, 2006; Michel & Curry, 1999; Huxley & Rumbaut, 2000 for reviews). The mechanisms by which these parameters are regulated have been theorized as changes in the size or shape of ‘pores’ through which the fluid and solutes travel or changes in the number of pores available. In reality, this oversimplified view does not account for several physiological and pathophysiological observations and fails to include all of the relevant, but as yet not fully studied, structures present at the microscopic level that may restrict or enable solute and/or fluid transport.

Structures contributing to the regulation of microvascular exchange

A cross section of a capillary viewed at the electron microscopic level displays several structural components that influence microvessel permeability. Interendothelial gaps serve as one route for small solutes and water to take. Vesicles are also present in the endothelium, and may either traffic solute from one side to the other or they may fuse to create transendothelial pores that allow microvascular exchange to occur freely for the time they exist. Endothelial cells possess a layer of secreted glycoproteins and glycolipids on their luminal surface that are arranged in a fibre matrix and are highly negatively charged. Named the glycocalyx, this barrier restricts solute movement not only physically, but also chemically because negatively charged proteins, such as albumin, will be repelled. The endothelial layer itself may regulate the permeability to solute and water by contracting or relaxing, thus modulating the width of interendothelial channels. Finally, perivascular mural cells called pericytes may similarly change the shape of the endothelial layer by contracting and relaxing.

Concepts of network microvascular exchange

The traditional views that arterioles do not contribute to microvascular exchange due to their thick smooth muscle layer, that venules are the main site for exchange of macromolecules owing to their large surface area and low flow, and that capillaries contribute predominantly to fluid filtration, are now beginning to wane in light of more recent data to the contrary. Now it has been demonstrated that arterioles do contribute to exchange, and that both solute and fluid exchange occur significantly across capillary and venular walls.

Contrary to the conventional view, permeability is not a constant value for an entire network or even a single vessel as illustrated in Fig. 1. As permeability is regulated by several mechanisms, this property of the microvasculature is subject to change (over space and time) depending upon the health of the surrounding tissue and to what drugs or signalling peptides the vessel is exposed (Huxley et al. 1997). Indeed, the permeability (both for fluid, Huxley et al. 1987, and solute, McKay & Huxley, 1995) may change within seconds upon exposure to atrial natriuretic peptide (ANP), a peptide hormone released during congestive heart failure. ANP doubles microvessel permeability, a change more than sufficient to cause a fluid shift into the interstitium. Further evidence for vascular permeability as a regulated parameter comes from quantitative studies of ‘normal’ vessels within the mesenteric vasculature that yield a non-normal (left-skewed) distribution of Ps values (see Figs 1, 2 and 5). Because some vessels within the network are ‘leakier’ than others, it can be argued that permeability is on a continuum subject to moment-to-moment regulation so that some vessels are set at a higher permeability than others in the network, which may reflect the metabolic need of the immediate tissue. In the inflammatory process, leukocyte–endothelial interactions may directly stimulate an increase in vascular permeability which facilitates leukocyte transmigration via intercellular adhesion molecule (ICAM-1)-dependent mechanisms (Sumagin et al. 2008).

Figure 1.

Figure 1

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Illustration of the distributed properties of basal, unstimulated microvessel protein permeability and fluid flux across the elements of the microvascular network. Permeability to albumin (Ps× 10−7 cm s−1) for arterioles and venules from skeletal muscle (SKM) of female (F) and male (M) rats (Wang, 2005; Wang & Huxley, 2006), and M mice (Sarelius et al. 2006), and coronary muscle of M and F pigs (Huxley et al. 2005, 2007) are plotted as the 5th, median and 95th percentiles, except for the mice which are the mean ± SEM. *P < 0.05.

Figure 2.

Figure 2

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Mesenteric collecting lymphatics in situ possess a finite value for basal permeability to autologous albumin and their basal permeability to rat serum does not differ from that of venules in the same tissue. The data from young male (M) rats (Scallan, 2010; Scallan & Huxley, 2010) are plotted as the 5th, 50th (median) and 95th percentiles illustrating the non-normal distribution of basal values. *P < 0.05.

Figure 5.

Figure 5

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Comparison of measures of rat collecting lymphatic and venule hydraulic conductivity (Lp) and permeability to albumin (Psalbumin). The data for the mesenteric collecting lymphatics of male (M) rats are from Scallan (2010). The hydraulic conductivities of the venules from mesentery of female (F, Zhou & He, 2010) and M (Adamson et al. 2008) rats are plotted as mean ± SEM. Psalbumin of mesenteric, skeletal muscle (SKM) and pig hearts, respectively (Huxley et al. 2005; Wang, 2005; Wang & Huxley, 2006) are plotted as the 5th, median and 95th percentiles; for mice SKM (Sarelius et al. 2006) the data are the mean ± SEM. *P < 0.05.

Role of the lymphatic vasculature in fluid homeostasis

Until now the blood microvasculature has been discussed as capable of handling both fluid filtration and reabsorption. Why, then, do we need a lymphatic vasculature? Many textbooks claim that fluid filtration occurs on the arterial side of the capillary vasculature with up to 90% of that filtrate being reabsorbed on the venous side of the circulation. More recently we have realized that the original Starling equation does not describe fluid transport adequately. Michel & Phillips (1987) proposed and validated an updated version of this equation from which it was concluded that fluid reabsorption does not occur across blood vessels due to their steady-state properties, i.e. constant pressure and flow produced by upstream arterioles (see earlier discussion). Consequently, the lymphatic vasculature provides the only escape route for extravasated fluid and macromolecules. Only in special states (e.g. oedema), in encapsulated organs (e.g. kidney), or the heart where pressures change often and rapidly may fluid be reabsorbed by the blood vasculature. Demonstrating its importance, early studies of the lymphatic vasculature indicated that almost the entire capillary filtrate is returned to the blood circulation by the thoracic duct (at the subclavian vein) and that diversion of this fluid results in the death of the animal from fluid loss (Drinker, 1938). Therefore, one may speculate that such an effective secondary vasculature possesses several mechanisms for the reabsorption of fluid and protein. First, a comparison of what is known about lymphatic microvessel structure relative to that of blood microvessels may elucidate potential pathways for fluid and protein transport.

Structures of the lymphatic vasculature contributing to exchange

The lymphatic vessels differ from blood microvessels in several significant ways. The two types of lymphatic vessels in the vicinity of the blood microvasculature and discussed here are lymphatic capillaries and larger collecting lymphatics. Lymphatic capillaries are ∼50 μm in diameter and do not possess a basement membrane, continuous interendothelial junctions, pericytes, or smooth muscle cells. Instead, they consist of a single layer of endothelial cells that overlap slightly with ‘button-like’ junctional protein expression, creating pores up to 2 μm in size allowing the one-way absorption of cells, fluid and proteins (Baluk et al. 2007). Collecting lymphatic vessels are larger in diameter (80–200 μm) and are vested with lymphatic muscle cells, possess continuous interendothelial junctions, and contain a thicker basement membrane. In addition, this type of lymphatic vessel is spontaneously contractile, with contraction frequencies averaging 20 s−1 in the rat (Scallan & Huxley, 2010). Whether or not either type of lymphatic vessel possesses a glycocalyx is, as yet, unknown. In the lymphatic vasculature it appears that the sole possible regulator of permeability is the lymphatic endothelium itself by contraction/relaxation, junctional rearrangement, or via vesicular transport.

Collecting lymphatic vessels as exchange vessels

Recently, one group demonstrated the origin of lymphatic endothelium by performing lineage tracing of Prox1, a gene encoding a transcription factor that demarcates lymphatic endothelium from blood endothelium (Srinivasan et al. 2007). Their conclusion was that lymphatic endothelial cells are derived solely from venous endothelium throughout embryonic development. Based on this finding, we hypothesized that lymphatic and blood endothelium must share many similar genes, although some are likely to be down- or up-regulated, and would probably express similar functions as well. We tested the novel hypothesis that collecting lymphatic vessels, the most similar type to blood microvessels, possessed a Ps to albumin that does not differ from that of venules, for which much data exist already (Scallan & Huxley, 2010).

For this study (Scallan & Huxley, 2010) several independent measures of collecting lymphatic vessel and venular permeability to albumin were made. When these measures are graphed (Fig. 2) it is apparent that both vasculatures possess a non-normal distribution of Ps values. For net tissue fluid homeostasis to exist, an implication of the data is that distributions of permeability values, exchange elements, and driving pressures are required. How this state is achieved has yet to be addressed. A second goal of this work was to measure Ps at several hydrostatic pressures. If the only process by which solute moves across the barrier is by simple diffusion, according to Fick's First Law, flux would not change with changing hydrostatic pressure and permeability to the solute would be a constant. If instead both fluid and solute can move through common pathways, a non-linear but positive increase in flux with increasing pressure (i.e. convection, Michel & Phillips, 1987; Levick & Michel, 2010) would be observed. Analysis of these data permits determination of the diffusive permeability (Pd) for the vessel (Huxley & Curry, 1991). When this analysis was performed, solute flux in the collecting lymphatics is coupled to fluid flux and Pd values of mesenteric collecting lymphatics and mesenteric venules do not differ (Fig. 3, Scallan & Huxley, 2010).

Figure 3.

Figure 3

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The theoretical relationships between albumin flux (A) and fluid flux (B) for mesenteric collecting lymphatics based on measures of exchange (Scallan, 2010; Scallan & Huxley, 2010) are given to illustrate that both protein and fluid flux from these vessels can change as the pressure within the lymphatics change either with intrinsic beating of the vessel or in response to changes in tissue pressure. The dashed arrow (labelled σΔπ) intersecting the pressure axis is the pressure at which no fluid movement will occur and is calculated from the measures of total protein content of the mesenteric fluid (Scallan & Huxley, 2010); at this pressure the value of solute flux is that of the true diffusive permeability (Pd). The limiting slope (continuous line, A) is equal to Lp(1 –σ). In B, the thin continuous straight line is the relationship of fluid flux assuming non-steady-state conditions as stated by the modern form of the Starling equation suggesting filtration from the collecting lymphatics at pressures above, and reabsorption of fluid at pressures below, σΔπ. In contrast, the continuous, non-linear thick line describes the steady-state relationship which implies negligible to low fluid filtration at all pressures and only transient reabsorption at pressures below σ2Δπ (Michel & Phillips, 1987). Given that the collecting lymphatics contract, pressures within the lymph angions will rise and fall making it possible for non-steady conditions to predominate in a healthy vessel.

Of greater interest, however, was the direction of solute movement determined from measures of total protein and albumin in samples of plasma, lymph and interstitial fluids. The total protein and albumin concentrations of lymph were greater than those in the interstitial space demonstrating that solute was diffusing out of the lymphatic vessel into the surrounding tissue (Fig. 4), just as an exchange vessel would be expected to behave. Finally, when all of these data were used to model fluid transport of the ‘average’ lymphatic vessel, it was determined that instead of following the steady-state model of fluid filtration, the constantly contracting lymphatic vessels (frequency given earlier) are experiencing constant fluctuations in hydrostatic pressure suggesting that they follow the classical Starling model, where both fluid filtration and reabsorption are possible, depending on the balance of hydrostatic and oncotic forces. The final results of the modelling suggest that for ‘average’ collecting lymphatic vessels, fluid reabsorption is possible at low pressure gradients (<∼2 cmH2O; Scallan & Huxley, 2010).

Figure 4.

Figure 4

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Illustration of the protein and albumin levels measured in young male rat plasma, mesenteric tissue fluid immediately following surgery, and collecting lymphatic fluid following vessel cannulation (Scallan, 2010; Scallan & Huxley, 2010). The expectation had been that the concentration (C) in the collecting lymph equals that of the interstitial fluid which would be significantly lower than that of the plasma. Instead, both total protein and albumin levels (bars, mean ± SEM) of the collecting lymphatic were significantly higher than that of the interstitial fluid and the proportion of total protein which was albumin differed in the 3 compartments (64%, 30% and 41% of the plasma, peritoneal and collecting lymphatic fluid, respectively; Scallan, 2010). The oncotic pressures, calculated from the Landis–Pappenheimer equation (Landis & Pappenheimer, 1963) for total protein and albumin, respectively, are plotted as filled circles.

In addition, newer research on the responses of collecting lymphatic permeability to vasoactive agents has lead to unexpected results (Scallan, 2010). Again like the venules, collecting lymphatic permeability to albumin is doubled within minutes of exposure to atrial or brain natriuretic peptides (ANP and BNP, respectively). However, while both peptides increase permeability to the same extent in lymphatic vessels, the spontaneous contractions of the vessels are regulated oppositely by these two peptides. ANP potently inhibited the spontaneous contractions, while BNP accelerated the contraction frequency and amplitude.

Implications for critical care

During oedema (pulmonary, myocardial, shock etc.) excess fluid accumulates in the interstitium and must be drained by the lymphatic vasculature. If the oedema originates from increases in blood microvascular permeability, and tissue pressure is elevated, it may be proposed that a change in pressures or permeability, or both, could lead to more efficient fluid reabsorption across the lymphatic endothelium. One mechanism is via the ability of the collecting lymphatics to act as Starling resistors increasing force of contraction (Nicoll & Taylor, 1977), or by losing contractions completely to act instead as passive conduits for fluid transport (Zawieja et al. 2008). In this instance, any increases in lymphatic Ps would be expected to increase the rate of fluid reabsorption. Therefore, drugs that augment lymphatic permeability and or increase lymphatic contractions may be desired for the treatment of oedema.

Oedema may also be a compensatory mechanism in chronic disease states such as in chronic heart failure (CHF), where patients experience a fluid shift into the interstitium to decrease the vascular volume. The fluid shift in CHF is mediated by release of ANP and BNP, two peptide hormones that act to increase capillary permeability and natriuresis (Chen & Burnett, 2000). However, by potently increasing lymphatic vessel permeability at the same time, fluid and protein extravasated by the microvasculature are unable to return to the bloodstream by the thoracic duct, thereby trapping water in the interstitium.

Future research questions

Now that we are aware that collecting lymphatics participate in the net exchange of fluid and solute and possess features similar to those of venules, multiple questions arise. It appears that the terminal lymphatic sacs in the tissue are passive structures anchored to the interstitial matrix and that fluids and solutes passing into them is a consequence of mechanical processes (Clough & Smaje, 1978; Schmid-Schönbein, 1990; Negrini & Del Fabbro, 1999; Zawieja, 2009) resulting in small transient changes in pressure that provide the propulsive force. Beyond this information the exchange characteristics of the endothelium lining these passages is not known nor is it known whether the barrier properties are static or change in response to changes in the tissue environment. Given that the collecting lymphatics in the mesentery in young male animals possess characteristics similar to venules in the same tissue (Scallan, 2010; Scallan & Huxley, 2010; Fig. 5), whether the result can be applied to these vessels in other organs is also unknown. Nor is it known whether the sexual dimorphisms identified to date for venules in heart (Huxley et al. 2005, 2007; Fig. 5) and skeletal muscle (Wang, 2005, Fig. 5) will also hold true for the collecting lymphatics. Especially interesting is that while basal exchange in venules was sex-independent in the heart (Fig. 5) it is the venules that demonstrated the most dramatic sex-dependent changes in basal permeability properties in response to endurance exercise training (Huxley et al. 2007) and in response to the presence of adenosine (Huxley et al. 2005; Wang, 2005; Huxley & Wang, 2010).

We do not know how lymphatic endothelium responds in acute or chronic inflammation (Aird, 2007a,b;), during tissue healing, or in the presence of chronic fluid retention. As we find that lymphatic exchange can be altered acutely to vasoactive agents such as the natriuretic peptides, can we expect permeability (as it does for capillaries: Huxley et al. 1993) and lymphatic pumping (frequency and force of contraction: Benoit, 1997) to change in the face of increases of adrenergic agents used commonly in the treatment of sepsis or cardiogenic shock? Of even greater interest is, what are the contributions of the lymphatic endothelium and lymphatic exchange to the development of complex chronic disease states, especially heart failure, insulin resistance, or type II diabetes, all circumstances known to result in fluid imbalance? In venous microvascular exchange, it is known that a significant barrier to solute flux is the endothelial surface glycocalyx. Whether such a structure exists on the lymphatic endothelium has not been explored; no less whether its characteristics change with alterations in the fluid milieu. It is known that arteriolar smooth muscle function can be regulated and modified as a consequence of interactions with the constituents of the tissue matrix (Hocking et al. 2008; Sun et al. 2008; Reed & Rubin, 2010). By analogy, given the intimate association of the lymphatics with the tissue matrix, could not similar mechanisms play important roles in lymphatic dysfunction or the ability to rapidly resolve oedema as can occur in idiopathic (Dhir et al. 2007) and systemic capillary leak syndromes (Druey & Greipp, 2010)? Finally, little is known of lymphatic vessel pharmacology or how their structure and function change with age.

Acknowledgments

The authors are supported by grant funds from NASA and NIH.

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