Lymph Flux Research Articles

Computational Modeling of Lymph Filtration and Absorption in the Lymph Node by Boundary Integral Equations

We develop a numerical method for solving three-dimensional problems of fluid filtration and absorption in a piecewise homogeneous medium by means of boundary integral equations. This method is applied to a simulation of the lymph flow in a lymph node. The lymph node is considered as a piecewise homogeneous domain containing porous media. The lymph flow is described by Darcy’s law. Taking into account the lymph absorption, we propose an integral representation for the velocity and pressure fields, where the lymph absorption imitates the lymph outflow from a lymph node through a system of capillaries. The original problem is reduced to a system of boundary integral equations, and a numerical algorithm for solving this system is provided. We simulate the lymph velocity and pressure as well as the total lymph flux. The method is verified by comparison with experimental data.

Critical Issues in Modelling Lymph Node Physiology

In this study, we discuss critical issues in modelling the structure and function of lymph nodes (LNs), with emphasis on how LN physiology is related to its multi-scale structural organization. In addition to macroscopic domains such as B-cell follicles and the T cell zone, there are vascular networks which play a key role in the delivery of information to the inner parts of the LN, i.e., the conduit and blood microvascular networks. We propose object-oriented computational algorithms to model the 3D geometry of the fibroblastic reticular cell (FRC) network and the microvasculature. Assuming that a conduit cylinder is densely packed with collagen fibers, the computational flow study predicted that the diffusion should be a dominating process in mass transport than convective flow. The geometry models are used to analyze the lymph flow properties through the conduit network in unperturbed- and damaged states of the LN. The analysis predicts that elimination of up to 60%–90% of edges is required to stop the lymph flux. This result suggests a high degree of functional robustness of the network.

Visualising lymph movement in anuran amphibians with computed tomography.

Lymph flux rates in anuran amphibians are high relative to those of other vertebrates owing to 'leaky' capillaries and a high interstitial compliance. Lymph movement is accomplished primarily by specialised lymph muscles and lung ventilation that move lymph through highly compartmentalised lymph sacs to the dorsally located lymph hearts, which are responsible for pumping lymph into the circulatory system; however, it is unclear how lymph reaches the lymph hearts. We used computed tomography (CT) to visualise an iodinated contrast agent, injected into various lymph sacs, through the lymph system in cane toads (Rhinella marina). We observed vertical movement of contrast agent from lymph sacs as predicted, but the precise pathways were sometimes unexpected. These visual results confirm predictions regarding lymph movement, but also provide some novel findings regarding the pathways for lymph movement and establish CT as a useful technique for visualising lymph movement in amphibians.

Spontaneous activity in peripheral diaphragmatic lymphatic loops

The spontaneous contractility of FITC-dextran-filled lymphatics at the periphery of the pleural diaphragm was documented for the first time "in vivo" in anesthetized Wistar rats. We found that lymphatic segments could be divided into four phenotypes: 1) active, displaying rhythmic spontaneous contractions (51.8% of 197 analyzed sites); 2) stretch-activated, whose contraction was triggered by passive distension of the vessel lumen (4.1%); 3) passive, which displayed a completely passive distension (4.5%); and 4) inert, whose diameter never changed over time (39.6%). Smooth muscle actin was detected by immunofluorescence and confocal microscopy in the vessel walls of active but also of inert sites, albeit with a very different structure within the vessel wall. Indeed, while in active segments, actin was arranged in a dense mesh completely surrounding the lumen, in inert segments actin decorated the vessels wall in sparse longitudinal strips. When located nearby along the same lymphatic loop, active, stretch-activated, and passive sites were always recruited in temporal sequence starting from the active contraction. The time delay was ∼0.35 s between active and stretch-activated and 0.54 s between stretch-activated and passive segments, promoting a uniform lymph flux of ∼150/200 pl/min. We conclude that, unlike more central diaphragmatic lymphatic vessels, loops located at the extreme diaphragmatic periphery do require an intrinsic pumping mechanism to propel lymph centripetally, and that such an active lymph propulsion is attained by means of a complex interplay among sites whose properties differ but are indeed able to organize lymph flux in an ordered fashion.

Evolutionary implications of the distribution and variation of the skeletal muscles of the anuran lymphatic system

Lymphatic return to the circulation in anurans is dependent upon the interaction of a number of skeletal muscles and lung deflation. We define character states and describe variation of these putative lymphatic skeletal muscles: the M. cutaneus pectoris (CP), M. cutaneus dorsi (CD), M. piriformis (P), M. sphincter ani cloacalis (SAC), and the complex of the M. gracilis minor/M. abdominal crenator (GM/AC). We include examination of over 400 specimens of 377 species belonging to 40 of the 42 currently recognized anuran families. Some muscles show limited variation (P) or are clearly linked to phylogeny (CP; CD) and thus have limited value in the determination of form and function. However, the GM/AC and SAC show a high degree of structural variation that appears in taxa across the phylogenetic spectrum. This allows us to make phylogenetically independent determinations of form and function. We define an ancestral state of the GM and conclude that evolution of the GM/AC and SAC has progressed in two directions from this ancestral state: toward either elaboration or reduction. Where present, the character states of both of these muscle groups were observed in all species examined and the number of states correlated within each family as well. The degree of development of the GM/AC and SAC compliance pump system is strongly correlated with previously determined lymph flux rates in a three species test. Our data suggest there may be a relationship between greater elaboration of the GM/AC and SAC system and terrestriality among the Anura.Electronic supplementary materialThe online version of this article (doi:10.1007/s00435-013-0190-7) contains supplementary material, which is available to authorized users.

Lung ventilation is an effector of the baroreflex in the cane toad (Rhinella marina)

Lung ventilation plays an important role for regulating lymph flux in anurans by changing the compliance of lymph sacs that surround the lungs during changes in lung volume. Because lymph mobilization in anurans is dependent upon blood volume/pressure status, we hypothesized that lung ventilation, like cardiac and lymph heart effectors, is also an effector of the baroreflex. We tested this hypothesis by measuring lung ventilation frequency (fR) and heart rate (HR) while increasing mean arterial blood pressure (MAP) with phenylephrine (Phe; 0.05–1.0 mg/kg, i.v.) and decreasing MAP with sodium nitroprusside (SNP; 0.05–1.0 mg/kg, i.v.). Decreasing MAP with SNP resulted in a significant increase in fR by an average of 12 breaths min−1 while increasing MAP with Phe decreased fR by an average of 4 breaths min−1. The slope of the baroreflex gain (ΔHR/ΔMAP; beats min−1 kPa−1) for combined Phe and SNP injections was −3.9 ± 0.9 (r2 =0.54; P<0.001) and was similar to the slope of the relationship between ΔfR and ΔMAP (−5.2 ± 0.8; r2 = 0.69; P<0.001). These results suggest that lung ventilation is regulated by MAP, in addition to blood gases and pH, and is an effector of the baroreflex. Supported by NSF‐IOS 0843082.

Lymphatic pump manipulation mobilizes inflammatory mediators into lymphatic circulation

Lymph stasis can result in edema and the accumulation of particulate matter, exudates, toxins and bacteria in tissue interstitial fluid, leading to inflammation, impaired immune cell trafficking, tissue hypoxia, tissue fibrosis and a variety of diseases. Previously, we demonstrated that osteopathic lymphatic pump techniques (LPTs) significantly increased thoracic and intestinal duct lymph flow. The purpose of this study was to determine if LPT would mobilize inflammatory mediators into the lymphatic circulation. Under anesthesia, thoracic or intestinal lymph of dogs was collected at resting (pre-LPT), during four minutes of LPT, and for 10 min following LPT (post-LPT), and the lymphatic concentrations of interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-γ, tissue necrosis factor α, monocyte chemotactic protein-1 (MCP-1), keratinocyte chemoattractant, superoxide dismutase (SOD) and nitrotyrosine (NT) were measured. LPT significantly increased MCP-1 concentrations in thoracic duct lymph. Further, LPT increased both thoracic and intestinal duct lymph flux of cytokines and chemokines as compared with their respective pre-LPT flux. In addition, LPT increased lymphatic flux of SOD and NT. Ten minutes following cessation of LPT, thoracic and intestinal lymph flux of cytokines, chemokines, NT and SOD were similar to pre-LPT, demonstrating that their flux was transient and a response to LPT. This re-distribution of inflammatory mediators during LPT may provide scientific rationale for the clinical use of LPT to enhance immunity and treat infection.

Pulmonary compliance and lung volume varies with ecomorphology in anuran amphibians: implications for ventilatory-assisted lymph flux

Vertical movement of lymph from ventral regions to the dorsally located lymph hearts in anurans is accomplished by specialized skeletal muscles working in concert with lung ventilation. We hypothesize that more terrestrial species with greater lymph mobilization capacities and higher lymph flux rates will have larger lung volumes and higher pulmonary compliance than more semi-aquatic or aquatic species. We measured in situ mean and maximal compliance (Δvolume/Δpressure), distensibility (%Δvolume/Δpressure) and lung volume over a range of physiological pressures (1.0 to 4.0 cmH(2)O) for nine species of anurans representing three families (Bufonide, Ranidae and Pipidae) that span a range of body masses and habitats from terrestrial to aquatic. We further examined the relationship between these pulmonary variables and lymph flux for a semi-terrestrial bufonid (Rhinella marina), a semi-aquatic ranid (Lithobates catesbeianus) and an aquatic pipid (Xenopus laevis). Allometric scaling of pulmonary compliance and lung volume with body mass showed significant differences at the family level, with scaling exponents ranging from ∼0.75 in Bufonidae to ∼1.3 in Pipidae. Consistent with our hypothesis, the terrestrial Bufonidae species had significantly greater pulmonary compliance and greater lung volumes compared with semi-aquatic Ranidae and aquatic Pipidae species. Pulmonary distensibility ranged from ∼20 to 35% cmH(2)O(-1) for the three families but did not correlate with ecomorphology. For the three species for which lymph flux data are available, R. marina had a significantly higher (P<0.001) maximal compliance (84.9±2.7 ml cmH(2)O(-1) kg(-1)) and lung volume (242.1±5.5 ml kg(-1)) compared with L. catesbeianus (54.5±0.12 ml cmH(2)O(-1) kg(-1) and 139.3±0.5 ml kg(-1)) and X. laevis (30.8±0.7 ml cmH(2)O(-1) kg(-1) and 61.3±2.5 ml kg(-1)). Lymph flux rates were also highest for R. marina, lowest for X. laevis and intermediate in L. catesbeianus. Thus, there is a strong correlation between pulmonary compliance, lung volume and lymph flux rates, which suggests that lymph mobilization capacity may explain some of the variation in pulmonary compliance and lung volume in anurans.

Interspecific Comparisons of Lymph Volume and Lymphatic Fluxes: Do Lymph Reserves and Lymph Mobilization Capacities Vary in Anurans from Different Environments?

The femoral lymph sac volumes and lymph mobilization capacity were compared in three anuran species that span a range of environments, dehydration tolerance, ability to maintain blood volume with dehydration, and degrees of development of skeletal muscles putatively involved in moving lymph vertically to the posterior lymph hearts. The femoral lymph sac volume determined by Evans blue injection and dilution in the femoral lymph sac varied interspecifically. The semiaquatic species, Lithobates catesbeianus, had the greatest apparent lymph volume expressed either as 18.7 mL kg body mass⁻¹ or 94 mL kg thigh mass⁻¹, compared with both the terrestrial and aquatic species, Rhinella marina (7.3 mL kg body mass⁻¹ and 57 mL kg thigh mass⁻¹) and Xenopus laevis (6.5 mL kg body mass⁻¹ and 40 mL kg thigh mass⁻¹, respectively. Injections of Evans blue into the subvertebral lymph sac, which communicates with both pairs of lymph hearts, yielded the highest rates of lymph return to the circulation in all three species. The most terrestrial species had a greater rate of lymphatic return from the subvertebral lymph sac, compared with the other two species. The rate of lymph flux from the femoral sac varied interspecifically and was correlated with the number and development of skeletal muscles involved in lymph movement. The results indicated that the three species differ in both the volume of lymph present and the capacity to return lymph. Lymph flux was correlated with habitat and the ability to maintain blood volume when challenged by dehydration or hemorrhage, whereas femoral lymph volume was not correlated with these factors.

Variation in pulmonary compliance and lung volume is associated with lymph mobilization capabilities in anuran amphibians

Lymph movement to dorsally-located lymph hearts in anurans is accomplished by specific skeletal muscles, lymph sac compliance and lung ventilation. We hypothesize that species with increased pulmonary compliance (Cpul) and lung volume (Vlung) will be more effective at changing lymph sac compliance and lymph mobilization. Thus, terrestrial species should have greater Cpul and Vlung compared with aquatic species. This study examined the variation in Cpul and Vlung in 18 anuran species representing 7 families that span a large range of body mass (M) and ecomorph types. Maximal lung compliance (Cmax) scaled to M0.77 (r2 = 48%) while Vlung scaled to M0.66 (r2 = 37%). Body shape did not explain the variation in Cmax and Vlung because there was a strong correlation between M and snout-vent length (r2 = 94%). Lymph flux rates, measured in a previous study, were highest in a terrestrial bufonid (Rhinella marina) compared with a semi-aquatic ranid (Lithobates catesbeianus) and an aquatic pipid (Xenopus laevis). Cmax and Vlung were significantly different between these three species with R. marina > L. catesbeianus > X. laevis; thus, there is a strong correlation between lymph flux rate and Cmax and Vlung. We suggest that the considerable variation in Cpul and Vlung is primarily explained by species' ecomorphology and related to lymph flux requirements in different environments. Supported by NSF-IOS 0843082.

Lymph flux rates from various lymph sacs in the cane toad Rhinella marina: an experimental evaluation of the roles of compliance, skeletal muscles and the lungs in the movement of lymph

A new method for quantitatively determining lymph flux from various lymphatic sacs of an anuran, the cane toad, was developed. This method used the dye dilution principle of C(i)V(i)=C(f)V(f) following injection of Evans Blue into specific lymph sacs and measuring its appearance in the venous circulation. The apparent lymph volume was 57 ml kg(-1). The greatest rate of lymph return (0.5-0.8 ml kg(-1) min(-1)) and best linear fit of Evans Blue appearance in the circulation with time followed injections into the subvertebral lymph sac, which has direct connections to both the anterior and posterior pairs of lymphatic hearts. Rate of lymph flux from the pair of posterior lymph hearts was three times greater than the anterior pair. Rates of lymph flux were only influenced by injection volume in the crural lymph sacs, implicating lymph sac compliance as the source of the pressure for lymph movement from these sacs. Femoral lymph sac fluxes were decreased by 60% following ablation of the tendons of the sphincter ani cloacalis, abdominal crenators and piriformis. This supports a role for these muscles in generating the pressure for vertical lymph movement. Femoral lymph sac fluxes were also decreased by 70% by the insertion of a coil in the subvertebral lymph sac, preventing normal compression and expansion of this sac by the lungs. This supports a role for lung ventilation in generating the pressure for vertical movement of lymph. Contrary to previous hypotheses, fluxes from the brachial sac were not influenced by insertion of the coil into the subvertebral sac. A haemorrhage equivalent to 50% of the blood volume did not change lymph flux rates from the femoral lymph sacs. These data provide the first experimental evidence that actual lymph fluxes in the cane toad Rhinella marina depend on lymph sac compliance, contraction of specific skeletal muscles and lung ventilation to move lymph laterally and vertically to the dorsally located lymphatic hearts.

Chylomicrons Promote Intestinal Absorption and Systemic Dissemination of Dietary Antigen (Ovalbumin) in Mice

BackgroundA small fraction of dietary protein survives enzymatic degradation and is absorbed in potentially antigenic form. This can trigger inflammatory responses in patients with celiac disease or food allergies, but typically induces systemic immunological tolerance (oral tolerance). At present it is not clear how dietary antigens are absorbed. Most food staples, including those with common antigens such as peanuts, eggs, and milk, contain long-chain triglycerides (LCT), which stimulate mesenteric lymph flux and postprandial transport of chylomicrons through mesenteric lymph nodes (MLN) and blood. Most dietary antigens, like ovalbumin (OVA), are emulsifiers, predicting affinity for chylomicrons. We hypothesized that chylomicron formation promotes intestinal absorption and systemic dissemination of dietary antigens.Methodology/Principal FindingsAbsorption of OVA into MLN and blood was significantly enhanced when OVA was gavaged into fasted mice together with LCT compared with medium-chain triglycerides (MCT), which do not stimulate chylomicron formation. The effect of LCT was blocked by the addition of an inhibitor of chylomicron secretion, Pluronic L-81. Adoptively transferred OVA-specific DO11.10 T-cells proliferated more extensively in peripheral lymph nodes when OVA was gavaged with LCT than with MCT or LCT plus Pluronic L-81, suggesting that dietary OVA is systemically disseminated. Most dietary OVA in plasma was associated with chylomicrons, suggesting that these particles mediate systemic antigen dissemination. Intestinal-epithelial CaCo-2 cells secreted more cell-associated, exogenous OVA when stimulated with oleic-acid than with butyric acid, and the secreted OVA appeared to be associated with chylomicrons.Conclusions/SignificancePostprandial chylomicron formation profoundly affects absorption and systemic dissemination of dietary antigens. The fat content of a meal may affect immune responses to dietary antigens by modulating antigen absorption and transport.

Ischemia–Reperfusion Does Not Cause Significant Hyaluronan Depolymerization in Skeletal Muscle

The size of hyaluronan in lymph and gastrocnemius muscle was measured to test the hypothesis that reperfusion of ischemic skeletal muscle leads to hyaluronan depolymerization. Prenodal lymph was collected from the gastrocnemius muscle in anesthetized rabbits. Hyaluronan size was measured using a combination of agarose gel electrophoresis and a radiometric assay. In control legs, muscle contained primarily high-molecular-weight hyaluronan (greater then 4 × 10 6), while lymph contained primarily low-molecular-weight hyaluronan (less than 0.79 × 10 6) which was absent from tissue. Following 3 h of ischemia and 8 h of reperfusion, the lymph flux for high-molecular-weight hyaluronan was 25 times the value from the control leg. Neither the size nor the content of hyaluronan in tissue decreased. Muscle albumin content from the reperfused leg was 2.3 times the value from the control leg, while lymph albumin flux was 4 times the control value. Measurements following 24 h of reperfusion confirmed the absence of changes in the size or content of hyaluronan in tissue although an increased albumin content and wet weight-to-dry weight ratio indicated sustained edema. The daily removal of hyaluronan by lymph was calculated to be 2–3% of the tissue content. Since the lymph drainage of hyaluronan represented only a very small fraction of tissue hyaluronan, the amount of depolymerization was too small to produce significant changes in the tissue.

TNF-alpha in smoke inhalation lung injury.

Adult respiratory distress syndrome is a major cause of morbidity in fire victims. Tumor necrosis factor-alpha(TNF-alpha) is edematogenic and has been associated with the etiology of other forms of adult respiratory distress syndrome. In the sheep lymph fistula model, we measured TNF-alpha after 48 (n = 7) or 128 (n = 3) breaths of cotton smoke and compared this with sham controls (n = 5) or controls in which left atrial pressure was elevated to 20 mmHg (n = 5) to increase lymph flow in the absence of inflammation. Smoke induced a rise in lymph flow and pulmonary arterial pressure with either no fall in lymph-to-plasma protein ratio (128 breaths) or a modest fall in lymph-to-plasma protein ratio (48 breaths), consistent with a change in microvascular permeability as well as a rise in microvascular pressure. Lymph concentration of TNF-alpha fell in both groups, although lymph flux (concentration x flow) transiently rose in both. In neither case did TNF-alpha flux exceed that induced by left atrial pressure elevation. TNF-alpha was detectable in only one out of five sheep in alveolar lavage. Thus, by utilizing a sensitive and specific radioimmunoassay, we were unable to demonstrate a role for TNF-alpha in smoke-induced microvascular lung injury in sheep.

Effects of intravenous pentafraction on lung and soft tissue liquid exchange in hypoproteinemic sheep.

Effects of infusing pentafraction (Pen), a synthetic hydroxyethyl starch plasma volume expander, on lung and soft tissue lymph flux were compared in nonanesthetized sheep that were protein depleted by batch plasmapheresis. Pen (5%) was infused to raise pulmonary arterial wedge pressure by 5 mmHg for 2 h (1.8 +/- 0.3 l). Pen raised plasma osmotic pressure from plasmapheresis baseline (10.7 +/- 2.2 mmHg; preplasmapheresis baseline, 19.6 +/- 0.6 mmHg) to 16.6 +/- 2.4 mmHg. After Pen, lung lymph flows peaked at 3.9 +/- 2.0 times a preplasmapheresis baseline value of 1.0 (plasmapheresis baseline, 2.7 +/- 0.7), but soft tissue lymph flows rose insignificantly. Plasma Pen concentrations were 2.3 +/- 1.0% postinfusion and 1.6 +/- 0.3% at 12 h. Pen mean molecular masses at these times, measured by high-performance liquid chromatography, were 160 +/- 44 and 129 +/- 23 kDa, respectively. In lung lymph, Pen concentrations were 0.8 +/- 0.6% postinfusion and 0.7 +/- 0.2% at 12 h, with mean molecular masses of 125 +/- 44 and 112 +/- 18 kDa, respectively. In soft tissue lymph Pen was nearly undetectable postinfusion, but at 12 h concentrations averaged 0.3 +/- 0.2% with a mean molecular mass of 80 +/- 10 kDa. The osmotic effectiveness of Pen may be related to its molecular mass, which was large enough to restrict filtration so that the plasma-to-lung lymph osmotic pressure gradient widened. Pen remained effective in the circulation for at least 24 h.

A simplified two-pore filtration model explains the effects of hypoproteinemia on lung and soft tissue lymph flux in awake sheep

We used a simplified two-pore filtration model to examine the effects of hypoproteinemia on lung and soft tissue lymph flux in awake sheep ( n = 7). To induce hypoproteinemia, we subjected each animal to 3 days of batch plasmapheresis (6 units per day). Data were collected in near steady-state conditions, 15–18 hr following completion of the last plasmapheresis episode. At this time, plasma protein concentration had fallen by 34%, while lung and soft tissue lymph protein concentrations had fallen by 55 and 62%, respectively. Lung and soft tissue lymph flows increased 52 and 87%, respectively. The plasma-to-lymph osmotic pressure gradients for lung and soft tissue lymph were unchanged by protein depletion (soft tissue, 7.7 mm Hg; lung, 4.8 mm Hg). We applied these results to a heteropore model of the microvascular barrier that consisted of two types of pores: those which plasma proteins could not cross (σ = 1) and those which proteins could cross without restriction (σ = 0). We varied the proportion of small pores to large pores until the measured data fit a model in which the calculated microvascular hydrostatic pressures in normal and hypoproteinemic conditions were equal. This was based on the assumption that microvascular hydrostatic pressure did not change with plasma protein depletion. These conditions could be satisfied when the small pores accounted for 90% of total barrier porosity. According to the model, lymph flow increased in hypoproteinemia because of an increase in protein-free liquid flux through the large percentage of small pores; protein flux through the small percentage of large pores remained unchanged. The net result was an increase in lymph flow and a decrease in the lymph protein concentration. The model reproduced these changes even though the plasma-to-lymph osmotic pressure gradients were unchanged. We conclude that a simplified heteropore model can explain the effects of hypoproteinemia on lung and soft tissue lymph flux.

Comparison of crosspoint and least-squares regression methods in computation of membrane protein flux parameters from lymph flux analysis

To compute two parameters of capillary protein transport of reflection coefficient (σ) and permeability-surface area product ( PS), two major methods have been employed. The first, or crosspoint method, uses two sets of lymph flow ( J v) and lymph/plasma protein concentration ratios ( R) and solves the irreversible thermodynamic relationship between σ and PS by simultaneous solution. The second, or least squares method, analyzes the total R versus J v curve by finding a best fit of all points to the irreversible thermodynamic relationship of R versus J v. Three theoretical membranes were analyzed with both methods by imposing random errors of 10 or 20% in R and J v. It was found that such errors, especially in R, were associated with substantial decreases in the percent of successful computations by the crosspoint method. In tight membranes (σ = 0.9) both methods gave comparable values. For intermediate (σ = 0.5) and loose membranes (σ = 0.2) the least-squares method was less specific than the crosspoint method, since up to 9% of random values of R and J v would be included within the 95% limits for the method. Moreover, attributing homogeneous variance to input data and sampling J v at geometric intervals exaggerated the variability of the least-squares method output parameters over those obtained by the crosspoint method. Because of nonspecificity, and the fact that the least squares method does not allow for the possibility that σ and PS are direct functions of hydrostatic capillary pressure or J v, the crosspoint method appears superior to the least-squares method for computation of σ and PS from R and J v.

New formulation of water and macromolecular flux which corrects for non-ideality: Theory and derivation, predictions, and experimental results

Classic irreversible formulation of coupled water and macromolecular transport across capillaries by Kedem & Katchalsky (1958), even with subsequent refinements (Spiegler & Kedem, 1966), assumes explicitly that colloid osmotic pressure (pi) is linearly related to macromolecular concentration. It is known, however, that pi is related to concentration by an accelerating function empirically expressed as a cubic equation (Landis & Pappenheimer, 1963). Using only basic rules of irreversible thermodynamics (Onsager, 1931), we rederived the coupled flux equations in exact form. To render them approximately solvable, we assumed mathematical continuity across the membrane and incorporated the Landis-Pappenheimer relationship. Results yielded equations giving different membrane descriptors from the classic formulation (CF). Instead of a sieving coefficient (1 - sigma), the new formulation (NF) gives a parameter A which is solute flux per unit volume flux when oncotic gradient is zero. Instead of a permeability-surface area product (PS), the NF gives a parameter phi which is solute flux per unit "solute pressure" at zero water flow. Relationships between sigma, PS, A, and phi are shown whereby differences between CF and NF can be investigated. Predictions were made comparing values expected from experiment for a variety of membrane descriptors and variables using either CF or NF. Predictions show that for any sets of lymph flux and lymph/protein concentration ratio, a number of inequalities are expected: For reflection coefficient, sigma NF greater than sigma CF; for PS, PSNF greater than PSCF; for mean relative membrane protein concentration, C/C p(NF) less than C/C p(CF); and for fraction of protein transport carried by permeative processes, Fr DNF greater than Fr DCF. In venous pressure perturbation experiments in the hindquarters of 21 dogs, the predictions were upheld. Moreover, CF values were not closely predictive of NF values. As others have noted, CF values of sigma and PS are correlated with capillary pressure or filtration; and this relationship is not obliterated by NF treatment, possibly indicating a true pressure or flow dependency of membrane descriptors.

Studies on kinetics of albumin in uraemic patients on chronic haemodialysis: evidence of interstitial albumin wash-down.

Albumin-kinetic studies were performed in nine uraemic patients without oedema on chronic haemodialysis and in seven normal controls in order to determine microvascular leakiness and thereby, during steady state, lymph drainage of albumin. Transvascular escape rate of albumin [TERalb i.e. the fraction of intravascular mass (IVMalb) passing into, or returning from, the extravascular space per unit time] and the distribution ratio (DRalb) between IVMalb and total albumin mass were determined from intravenously injected radioiodinated serum albumin. Before haemodialysis, TERalb was significantly elevated (mean 9 X 6% IVMalb h-1, range 5 X 9-14) as compared to the value 15 h after haemodialysis (mean 7 X 3, range 5 X 2-11, P less than 0 X 02) and to controls (mean 5 X 9, range 4 X 3-7 X 4, P less than 0 X 01). Average DRalb (mean 0 X 54, range 0 X 44-0 X 69) was clearly elevated in patients with respect to controls (mean 0 X 44, range 0 X 42-0 X 48, P less than 0 X 01), and the extravascular mass of albumin was significantly decreased (mean 27 X 9 mumol kg-1, range 14.1 - 41.2 v. mean 35.9, range 27.1 - 43.8, P less than 0.05). We interpret the results as to indicate increased transvascular filtration of albumin in microcirculatory beds with permeable capillaries (splanchnic organs), in between the haemodialysis treatment, and filtration of protein-poor fluid in areas with 'tight' capillaries (skeletal muscle, cutis) resulting in interstitial space protein depletion here. As the patients were considered to be in steady state during the measurements, the increased TERalb indicates increased lymph flux of albumin. The interstitial space protein 'wash-down' and increased lymph drainage probably serve as oedema prevention.

Microvascular fluid and protein flux in pulmonary and systemic circulations after thermal injury

The local and generalized microvascular response to thermal injury, monitoring transvascular fluid flux and protein permeability in burned and nonburned soft tissue and in the lung, was studied. Chronic lymph fistulas were produced in lung and soft tissue in adult sheep. Lymph flux ( L ̇ ) and the lymph-to-plasma ( L P ) protein ratio for four protein fractions separated by gel electrophoresis, were used to monitor fluid flux and protein permeability before and for 72 hr after a 25% full-thickness skin burn. There was a marked increase in both ( L ̇ ) and the L P ratio for proteins ranging from 35- to 108-Å radius in burn tissue for the entire 72-hr period, indicating an increased protein permeability. There was a transient increase in ( L ̇ ) and L P for proteins 58 Å and less in nonburn tissue, with the permeability change lasting about 12 hr. Fluid flux was significantly increased in the lung for 24–36 hr, but protein sieving was normal as demonstrated by a decrease in L P ratio for all protein fractions, indicating the increase in ( L ̇ ) to be due to an increase in microvascular hydrostatic pressure.