Lymphatic fluid: exchange mechanisms and regulation

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.

Figure 1

Illustration of the distributed properties of basal, unstimulated microvessel protein permeability and fluid flux across the elements of the microvascular network. Permeability to albumin (P_s× 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

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

Comparison of measures of rat collecting lymphatic and venule hydraulic conductivity (L_p) and permeability to albumin (P_s^albumin). 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. P_s^albumin 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.

Figure 3

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 (P_d). The limiting slope (continuous line, A) is equal to L_p(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.

Figure 4

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.