Interstitial Fluid Balance Research Articles

Sustained ACE2 Expression by Probiotic Improves Integrity of Intestinal Lymphatics and Retinopathy in Type 1 Diabetic Model.

Intestinal lymphatic, known as lacteal, plays a critical role in maintaining intestinal homeostasis by regulating several key functions, including the absorption of dietary lipids, immune cell trafficking, and interstitial fluid balance in the gut. The absorption of dietary lipids relies on lacteal integrity, mediated by button-like and zipper-like junctions. Although the intestinal lymphatic system is well studied in many diseases, including obesity, the contribution of lacteals to the gut-retinal axis in type 1 diabetes (T1D) has not been examined. Previously, we showed that diabetes induces a reduction in intestinal angiotensin-converting enzyme 2 (ACE2), leading to gut barrier disruption. However, when ACE2 levels are maintained, a preservation of gut barrier integrity occurs, resulting in less systemic inflammation and a reduction in endothelial cell permeability, ultimately retarding the development of diabetic complications, such as diabetic retinopathy. Here, we examined the impact of T1D on intestinal lymphatics and circulating lipids and tested the impact of intervention with ACE-2-expressing probiotics on key aspects of gut and retinal function. Akita mice with 6 months of diabetes were orally gavaged LP-ACE2 (3x/week for 3 months), an engineered probiotic (Lactobacillus paracasei; LP) expressing human ACE2. After three months, immunohistochemistry (IHC) was used to evaluate intestinal lymphatics, gut epithelial, and endothelial barrier integrity. Retinal function was assessed using visual acuity, electroretinograms, and enumeration of acellular capillaries. LP-ACE2 significantly restored intestinal lacteal integrity as assessed by the increased expression of lymphatic vessel hyaluronan receptor 1 (LYVE-1) expression in LP-ACE2-treated Akita mice. This was accompanied by improved gut epithelial (Zonula occludens-1 (ZO-1), p120-catenin) and endothelial (plasmalemma vesicular protein -1 (PLVAP1)) barrier integrity. In Akita mice, the LP-ACE2 treatment reduced plasma levels of LDL cholesterol and increased the expression of ATP-binding cassette subfamily G member 1 (ABCG1) in retinal pigment epithelial cells (RPE), the population of cells responsible for lipid transport from the systemic circulation into the retina. LP-ACE2 also corrected blood-retinal barrier (BRB) dysfunction in the neural retina, as observed by increased ZO-1 and decreased VCAM-1 expression compared to untreated mice. LP-ACE2-treated Akita mice exhibit significantly decreased numbers of acellular capillaries in the retina. Our study supports the beneficial role of LP-ACE2 in the restoration of intestinal lacteal integrity, which plays a key role in gut barrier integrity and systemic lipid metabolism and decreased diabetic retinopathy severity.

Inflammation specific environment activated methotrexate-loaded nanomedicine to treat rheumatoid arthritis by immune environment reconstruction.

Rheumatoid arthritis (RA), as an autoimmune inflammatory disease, is featured by enhanced vascular permeability, irreversible cartilage destroys and bone erosion. Although the pathogenesis of RA is still unclear, the immune environment, particularly the lymphatic system, which is instrumental to immune cell surveillance and interstitial fluid balance, plays vital roles in the process of RA. Herein, an inflammation specific environment activated methotrexate-encapsulated nanomedicine (MTX@NPs) was constructed for RA treatment, which accumulated in inflamed joints, and released MTX in the specific RA microenvironment. Notably, MTX@NPs could regulate the immune environment including reducing the expressions of inflammatory cytokines of macrophages and the inflammatory level of lymphatic epithelial cells (LECs), and ameliorating the lymphatic vessel contraction and drainage. In vitro and In vivo studies illustrated that MTX@NPs exhibited a high RA therapeutic efficacy and insignificant systemic toxicity owing to the suppression of the inflammation response and the improved lymphatic functions of RA joints. It suggests that the nanomedicine paves a potential way to the clinical practice of autoimmune diseases treatments via the regulation of immune environment and lymphatic functions. STATEMENT OF SIGNIFICANCE: Although 1.0% of the population in the world suffers from rheumatoid arthritis (RA), the pathogenesis of RA is still unclear and the therapeutic effect of the first-line clinical drugs is relatively low. Herein, we propose a specific RA-microenvironment triggered nanomedicine (MTX@NPs), which enhances RA treatment of a first-line antirheumatic drug (methotrexate, MTX) by immune environment reconstruction. The nanomedicine exhibits RA joints accumulation by EPR effect, and releases MTX under the specific RA environment, leading to the dramatical drop of M1-type macrophages and acceleration of lymphatic vessel contraction and drainage. Finally, the inflammatory cytokines in RA immune environment are reduced sharply, indicating the outstanding therapeutic efficacy of MTX@NPs to RA.

Pulmonary Interstitial Matrix and Lung Fluid Balance From Normal to the Acutely Injured Lung.

This review analyses the mechanisms by which lung fluid balance is strictly controlled in the air-blood barrier (ABB). Relatively large trans-endothelial and trans-epithelial Starling pressure gradients result in a minimal flow across the ABB thanks to low microvascular permeability aided by the macromolecular structure of the interstitial matrix. These edema safety factors are lost when the integrity of the interstitial matrix is damaged. The result is that small Starling pressure gradients, acting on a progressively expanding alveolar barrier with high permeability, generate a high transvascular flow that causes alveolar flooding in minutes. We modeled the trans-endothelial and trans-epithelial Starling pressure gradients under control conditions, as well as under increasing alveolar pressure (Palv) conditions of up to 25 cmH2O. We referred to the wet-to-dry weight (W/D) ratio, a specific index of lung water balance, to be correlated with the functional state of the interstitial structure. W/D averages ∼5 in control and might increase by up to ∼9 in severe edema, corresponding to ∼70% loss in the integrity of the native matrix. Factors buffering edemagenic conditions include: (i) an interstitial capacity for fluid accumulation located in the thick portion of ABB, (ii) the increase in interstitial pressure due to water binding by hyaluronan (the “safety factor” opposing the filtration gradient), and (iii) increased lymphatic flow. Inflammatory factors causing lung tissue damage include those of bacterial/viral and those of sterile nature. Production of reactive oxygen species (ROS) during hypoxia or hyperoxia, or excessive parenchymal stress/strain [lung overdistension caused by patient self-induced lung injury (P-SILI)] can all cause excessive inflammation. We discuss the heterogeneity of intrapulmonary distribution of W/D ratios. A W/D ∼6.5 has been identified as being critical for the transition to severe edema formation. Increasing Palv for W/D > 6.5, both trans-endothelial and trans-epithelial gradients favor filtration leading to alveolar flooding. Neither CT scan nor ultrasound can identify this initial level of lung fluid balance perturbation. A suggestion is put forward to identify a non-invasive tool to detect the earliest stages of perturbation of lung fluid balance before the condition becomes life-threatening.

Biochemical and mechanical signals in the lymphatic vasculature.

Lymphatic vasculature is an integral part of the cardiovascular system where it maintains interstitial fluid balance. Additionally, lymphatic vasculature regulates lipid assimilation and inflammatory response. Lymphatic vasculature is composed of lymphatic capillaries, collecting lymphatic vessels and valves that function in synergy to absorb and transport fluid against gravitational and pressure gradients. Defects in lymphatic vessels or valves leads to fluid accumulation in tissues (lymphedema), chylous ascites, chylothorax, metabolic disorders and inflammation. The past three decades of research has identified numerous molecules that are necessary for the stepwise development of lymphatic vasculature. However, approaches to treat lymphatic disorders are still limited to massages and compression bandages. Hence, better understanding of the mechanisms that regulate lymphatic vascular development and function is urgently needed to develop efficient therapies. Recent research has linked mechanical signals such as shear stress and matrix stiffness with biochemical pathways that regulate lymphatic vessel growth, patterning and maturation and valve formation. The goal of this review article is to highlight these innovative developments and speculate on unanswered questions.

Functional lymphatic reserve capacity is depressed in patients with a Fontan circulation.

BackgroundLymphatic abnormalities play a role in effusions in individuals with a Fontan circulation. Recent results using near‐infrared fluorescence imaging disclosed an increased contraction frequency of lymphatic vessels in Fontan patients compared to healthy controls. It is proposed that the elevated lymphatic pumping seen in the Fontan patients is necessary to maintain habitual interstitial fluid balance. Hyperthermia has previously been used as a tool for lymphatic stress test. By increasing fluid filtration in the capillary bed, the lymphatic workload and contraction frequency are increased accordingly. Using near‐infrared fluorescence imaging, the lymphatic functional reserve capacity in Fontan patients were explored with a lymphatic stress test.MethodsFontan patients (n = 33) were compared to a group of 15 healthy individuals of equal age, weight, and gender. The function of the superficial lymphatic vessels in the lower leg during rest and after inducing hyperthermia was investigated, using near‐infrared fluorescence imaging.ResultsBaseline values in the Fontan patients showed a 57% higher contraction frequency compared to the healthy controls (0.4 ± 0.3 min−1 vs. 0.3 ± 0.2 min−1, p = 0.0445). After inducing stress on the lymphatic vessels with hyperthermia the ability to increase contraction frequency was decreased in the Fontan patients compared to the controls (0.6 ± 0.5 min−1 vs. 1.2 ± 0.8 min−1, p = 0.0102).ConclusionsFontan patients had a higher lymphatic contraction frequency during normal circumstances. In the Fontan patients, the hyperthermia response is dampened indicating that the functional lymphatic reserve capacity is depressed. This diminished reserve capacity could be part of the explanation as to why some Fontan patients develop late‐onset lymphatic complications.

The lymphatic drainage system of the CNS plays a role in lymphatic drainage, immunity, and neuroinflammation in stroke

The lymphatic drainage system of the central nervous system (CNS) plays an important role in maintaining interstitial fluid balance and regulating immune responses and immune surveillance. The impaired lymphatic drainage system of the CNS might be involved in the onset and progression of various neurodegenerative diseases, neuroinflammation, and cerebrovascular diseases. A significant immune response and brain edema are observed after stroke, resulting from disrupted homeostasis in the brain. Thus, understanding the lymphatic drainage system of the CNS in stroke may lead to the development of new approaches for therapeutic interventions in the future. Here, we review recent evidence implicating the lymphatic drainage system of the CNS in stroke.

Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis.

Simple SummaryThe formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and show that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors.The formation of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels are major events associated with most epithelial malignancies, including breast cancer. Angiogenesis is essential for cancer cell survival. Lymphangiogenesis is critical in maintaining tumoral interstitial fluid balance and importing tumor-facilitatory immune cells. Both vascular routes also serve as conduits for cancer metastasis. Intratumoral hypoxia promotes both events by stimulating multiple angiogenic/lymphangiogenic growth factors. Studies on tumor-associated lymphangiogenesis and its exploitation for therapy have received less attention from the research community than those on angiogenesis. Inflammation is a key mediator of both processes, hijacked by many cancers by the aberrant expression of the inflammation-associated enzyme cyclo-oxygenase (COX)-2. In this review, we focus on breast cancer and showed that COX-2 is a major promoter of both events, primarily resulting from the activation of prostaglandin (PG) E receptor EP4 on tumor cells, tumor-infiltrating immune cells, and endothelial cells; and the induction of oncogenic microRNAs. The COX-2/EP4 pathway also promotes additional events in breast cancer progression, such as cancer cell migration, invasion, and the stimulation of stem-like cells. Based on a combination of studies using multiple breast cancer models, we show that EP4 antagonists hold a major promise in breast cancer therapy in combination with other modalities including immune check-point inhibitors.

The lymphatic system in alcohol-associated liver disease.

The lymphatic system plays vital roles in interstitial fluid balance and immune cell surveillance. The effect of alcohol on the lymphatic system is poorly understood. This review article explores the role of the lymphatic system in the pathogenesis of alcohol-related disease including alcoholic liver disease (ALD) and the therapeutic potential of targeting hepatic lymphatics for the treatment of ALD.

Linking lymphatic function to disease.

Lymphatic function is critical for maintaining interstitial fluid balance and is linked to multiple pathological conditions. Over the past 15 years, lymphatic research has re-emerged as an area of emphasis for vascular biologists wanting to understand the causes of oedema and the poor fluid drainage that are common denominators for various diseases (Breslin et al. 2018). Research has focused on two big questions: (1) How does fluid enter the lymphatic system? (2) How does fluid move through an initial lymphatic network? Interstitial fluid is thought to enter the lymphatic system through specialized intercellular junctions between endothelial cells of the initial lymphatic vessels. The fluid then passes into upstream collecting lymphatic vessels, also termed contractile vessels. These vessel segments, referred to as lympangions, are separated by intraluminal valves that prevent backflow of lymph. While current research has expanded to include coordination of lymphangion development, the active mechanism responsible for fluid flow from initial lymphatics to the collecting vessels and the involvement of immune cells, the mechanisms that control the frequency and force of contractions by lymphatic smooth muscle cells remain critical foci of investigation. Spontaneous smooth muscle cell contraction involves cell-surface receptors, ion fluxes and actin-myosin dynamics. As these mechanisms are essential for driving collecting vessel constriction and lymph flow, the discovery of new information has led to advancements in our understanding of how the lymphatic system works (Fig. 1). Basic science discoveries now motivate the challenge of linking new information to diseases. Perhaps, the more important question for lymphatic researchers and clinicians should be related to how our advanced understanding can impact treatment. In the current issue of The Journal of Physiology, work by Davis et al. (2020) provides an example of meeting this challenge by linking ATP sensitive smooth muscle specific potassium channel (KATP) dysfunction to Cantú syndrome, a rare disease associated with genetic mutation that alters potassium channel function and leads to lymphoedema. In the context of lymphatic function, the genetic mutation is considered to cause the potassium channels to be preferentially in the open state (Davis et al. 2020). The results by Davis et al. suggest that gain-of-function KATP subunit mutant mice also exhibit lymphatic contractile dysfunction, and that the inhibition of over-activity represents a therapeutic approach for reversing the effects. While a few studies have implicated the presence and a role for KATP channels in lymphatic vessels, the work by Davis et al. contributes cell-specific information regarding their role and a link to a disease state. The incorporation of studies with mutant mice, isolated vessels from humans, in vitro experiments, and multiple methodological approaches serve to provide novel mechanistic understanding of how a disease scenario can influence lymphatic fluid flow and in turn highlights why clinicians should be mindful about new basic research findings. The authors do not have any conflicts of interests on the submission. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. Funding was provided by NIH 1R01AG049821 awarded to W.L.M. and NIH 1R01GM120774 awarded to J.W.B.

A murine model of increased coronary sinus pressure induces myocardial edema with cardiac lymphatic dilation and fibrosis.

Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and hypertension. The aim of this study was to establish a murine model of myocardial edema and elucidate the response of cardiac lymphatics and the myocardium. Myocardial edema without infarction was induced in mice by cauterizing the coronary sinus, increasing pressure in the coronary venous system, and inducing myocardial edema. In male mice, there was rapid development of edema 3 h following coronary sinus cauterization (CSC), with associated dilation of cardiac lymphatics. By 24 h, males displayed significant cardiovascular contractile dysfunction. In contrast, female mice exhibited a temporal delay in the formation of myocardial edema, with onset of cardiovascular dysfunction by 24 h. Furthermore, myocardial edema induced a ring of fibrosis around the epicardial surface of the left ventricle in both sexes that included fibroblasts, immune cells, and increased lymphatics. Interestingly, the pattern of fibrosis and the cells that make up the fibrotic epicardial ring differ between sexes. We conclude that a novel surgical model of myocardial edema without infarct was established in mice. Cardiac lymphatics compensated by exhibiting both an acute dilatory and chronic growth response. Transient myocardial edema was sufficient to induce a robust epicardial fibrotic and inflammatory response, with distinct sex differences, which underscores the sex-dependent differences that exist in cardiac vascular physiology.NEW & NOTEWORTHY Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and high blood pressure. Cardiac lymphatics regulate interstitial fluid balance and, in a myocardial infarction model, have been shown to be therapeutically targetable by increasing heart function. Cardiac lymphatics have only rarely been studied in a noninfarct setting in the heart, and so we characterized the first murine model of increased coronary sinus pressure to induce myocardial edema, demonstrating distinct sex differences in the response to myocardial edema. The temporal pattern of myocardial edema induction and resolution is different between males and females, underscoring sex-dependent differences in the response to myocardial edema. This model provides an important platform for future research in cardiovascular and lymphatic fields with the potential to develop therapeutic interventions for many common cardiovascular diseases.

Fluid Osmolarity Acutely and Differentially Modulates Lymphatic Vessels Intrinsic Contractions and Lymph Flow.

Lymph formation and propulsion rely on an extrinsic mechanism based on the forces that surrounding tissues exert upon the vessel wall and lumen and an intrinsic mechanism based on spontaneous, rhythmic contractions of the lymphatic muscle layer of collecting vessels. The two spontaneous pacemakers described in literature involve chloride-dependent depolarizations (STDs) and If-like currents, both giving rise to a variable contraction frequency (fc) of lymphatic vessels functional units (lymphangions). Several stimuli have been shown to modulate fc, such as temperature, shear stress, and several tissue chemical modulators (prostaglandins, norepinephrine, acetylcholine, substance P, and others). However, no detailed description is present in literature on the acute modulation of fc by means of osmolarity change of the surrounding interstitial space. Using a well-developed ex-vivo rat diaphragmatic preparation, in which osmolarity was changed by varying the concentration of D-mannitol in the perfusing solution and in later experiments the concentration of NaCl and then of Na+ and Cl− ions separately by ionic substitution, we provide detailed experimental evidences that a stepwise increase in osmolarity from control value (308 mOsm) up to 324 mOsm caused a reduction of fc down to ~-70% within the first 14 min, and that a stepwise decrease in osmolarity up to 290 mOsm induced an early fc increase to ~+34% of control, followed by a decline to an fc of ~-18% of control value. These variations were more dramatic when the same osmolarity changes were obtained by varying NaCl and/or Na+ or Cl− ions concentration, which caused an almost complete arrest of spontaneous contractility within 14 min from the application. Diastolic and systolic diameters and stroke volume were not affected by osmolarity changes, so that modulation of lymph flow closely followed that of fc. Modulation of lymph flow secondary to osmolarity changes is relevant if one considers that interstitial fluid balance is also dependent upon lymph drainage, and thus it is possible that, at least in the acute phase following variations of interstitial fluid osmolarity, its volume control might eventually be impaired due to the reduced or in the worst scenario null lymph drainage.

Hepatic transudation barrier properties.

Fluid and protein continuously transude from the surface of the liver. Despite a common understanding that transudation plays a critical role in hepatic interstitial and peritoneal fluid balance, transudation from the entire liver has not been studied. Therefore, the goal of the present work was to provide the first direct measurement of the hepatic transudation rate and transudation barrier properties. Transudation rates were determined by collecting transudate from the entire liver. Hydraulic conductivity, and fluid transudation and protein reflection coefficients of the transudation barrier (formed by the subscapular interstitial matrix, capsule, and peritoneum) were determined from changes in fluid and protein transudation rates in response to hepatic venous pressure elevation. Following hepatic venous pressure elevation from 6.1±0.9 to11.1±0.6mm Hg, transudation rate increased from 0.13±0.03 to 0.37±0.03 mL/min·100g. Transudation barrier hydraulic conductivity, fluid transudation and protein reflection coefficients (3.9×10-4 ±5.7×10-5 mL/min·mm Hg·cm2 , 0.36±0.04mL/min·mm Hg, and 0.09±0.03, respectively) were comparable to those reported for hepatic sinusoids. Taken together, these findings suggest that the hepatic transudation barrier is highly permeable at elevated sinusoidal pressures. These fundamental studies provide a better understanding of the hepatic transudation barrier properties and transudation under conditions that are physiologically and clinically relevant to ascites formation.

Lymphatic Vessels: The Next Frontier in Lung Transplant.

Lymphatic vessels are essential for the uptake of fluid, immune cells, macromolecules, and lipids from the interstitial space. During lung transplant surgery, the pulmonary lymphatic vessel continuum is completely disrupted, and, as a result, lymphatic drainage function is severely compromised. After transplantation, the regeneration of an effective lymphatic drainage system plays a crucial role in maintaining interstitial fluid balance in the lung allograft. In the meantime, these newly formed lymphatic vessels are commonly held responsible for the development of immune responses leading to graft rejection, because they are potentially capable of transporting antigen-presenting cells loaded with allogeneic antigens to the draining lymph nodes. However, despite remarkable progress in the understanding of lymphatic biology, there is still a paucity of consistent evidence that demonstrates the exact impacts of lymphatic vessels on lung graft function. In this review, we examine the current literature related to roles of lymphatic vessels in the pathogenesis of lung transplant rejection.

Intestinal lymphatic vasculature: structure, mechanisms and functions.

The mammalian intestine is richly supplied with lymphatic vasculature, which has functions ranging from maintenance of interstitial fluid balance to transport of antigens, antigen-presenting cells, dietary lipids and fat-soluble vitamins. In this Review, we provide in-depth information concerning the organization and structure of intestinal lymphatics, the current view of their developmental origins, as well as molecular mechanisms of intestinal lymphatic patterning and maintenance. We will also discuss physiological aspects of intestinal lymph flow regulation and the known and emerging roles of intestinal lymphatic vessels in human diseases, such as IBD, infection and cancer.

Interstitial lung fluid balance in healthy lowlanders exposed to high-altitude

We aimed to assess lung fluid balance before and after gradual ascent to 5150m. Lung diffusion capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO) and ultrasound lung comets (ULCs) were assessed in 12 healthy lowlanders at sea-level, and on Day 1, Day 5 and Day 9 after arrival at Mount Everest Base Camp (EBC). EBC was reached following an 8-day hike at progressively increasing altitudes starting at 2860m. DLCO was unchanged from sea-level to Day 1 at EBC, but increased on Day 5 (11±10%) and Day 9 (10±9%) vs. sea-level (P≤0.047). DmCO increased from sea-level to Day 1 (9±6%), Day 5 (12±8%), and Day 9 (17±11%) (all P≤0.001) at EBC. There was no change in ULCs from sea-level to Day 1, Day 5 and Day 9 at EBC. These data provide evidence that interstitial lung fluid remains stable or may even decrease relative to at sea-level following 8days of gradual exposure to high-altitude in healthy humans.

Lymphatic pumping: mechanics, mechanisms and malfunction.

A combination of extrinsic (passive) and intrinsic (active) forces move lymph against a hydrostatic pressure gradient in most regions of the body. The effectiveness of the lymph pump system impacts not only interstitial fluid balance but other aspects of overall homeostasis. This review focuses on the mechanisms that regulate the intrinsic, active contractions of collecting lymphatic vessels in relation to their ability to actively transport lymph. Lymph propulsion requires not only robust contractions of lymphatic muscle cells, but contraction waves that are synchronized over the length of a lymphangion as well as properly functioning intraluminal valves. Normal lymphatic pump function is determined by the intrinsic properties of lymphatic muscle and the regulation of pumping by lymphatic preload, afterload, spontaneous contraction rate, contractility and neural influences. Lymphatic contractile dysfunction, barrier dysfunction and valve defects are common themes among pathologies that directly involve the lymphatic system, such as inherited and acquired forms of lymphoedema, and pathologies that indirectly involve the lymphatic system, such as inflammation, obesity and metabolic syndrome, and inflammatory bowel disease.

Estimation of the Pressure Drop Required for Lymph Flow through Initial Lymphatic Networks

Lymphatic function is critical for maintaining interstitial fluid balance and is linked to multiple pathological conditions. While smooth muscle contractile mechanisms responsible for fluid flow through collecting lymphatic vessels are well studied, how fluid flows into and through initial lymphatic networks remains poorly understood. The objective of this study was to estimate the pressure difference needed for flow through an intact initial lymphatic network. Pressure drops were computed for real and theoretical networks with varying branch orders using a segmental Poiseuille flow model. Vessel geometries per branch order were based on measurements from adult Wistar rat mesenteric initial lymphatic networks. For computational predications based on real network geometries and combinations of low or high output velocities (2 mm/s, 4 mm/s) and viscosities (1 cp, 1.5 cp), pressure drops were estimated to range 0.31-2.57 mmHg. The anatomical data for the real networks were also used to create a set of theoretical networks in order to identify possible minimum and maximum pressure drops. The pressure difference range for the theoretical networks was 0.16-3.16 mmHg. The results support the possibility for suction pressures generated from cyclic smooth muscle contractions of upstream collecting lymphatics being sufficient for fluid flow through an initial lymphatic network.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction.

The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology. Here, we investigate in rats the impact of MI and subsequent chronic heart failure on the cardiac lymphatic network. Further, we evaluate for the first time the functional effects of selective therapeutic stimulation of cardiac lymphangiogenesis post-MI. We investigated cardiac lymphatic structure and function in rats with MI induced by either temporary occlusion (n=160) or permanent ligation (n=100) of the left coronary artery. Although MI induced robust, intramyocardial capillary lymphangiogenesis, adverse remodeling of epicardial precollector and collector lymphatics occurred, leading to reduced cardiac lymphatic transport capacity. Consequently, myocardial edema persisted for several months post-MI, extending from the infarct to noninfarcted myocardium. Intramyocardial-targeted delivery of the vascular endothelial growth factor receptor 3-selective designer protein VEGF-CC152S, using albumin-alginate microparticles, accelerated cardiac lymphangiogenesis in a dose-dependent manner and limited precollector remodeling post-MI. As a result, myocardial fluid balance was improved, and cardiac inflammation, fibrosis, and dysfunction were attenuated. We show that, despite the endogenous cardiac lymphangiogenic response post-MI, the remodeling and dysfunction of collecting ducts contribute to the development of chronic myocardial edema and inflammation-aggravating cardiac fibrosis and dysfunction. Moreover, our data reveal that therapeutic lymphangiogenesis may be a promising new approach for the treatment of cardiovascular diseases.

Estimation of Pressure Drop Required for Lymph Flow through Initial Collecting Lymphatics

Lymphatic function is critical for maintaining interstitial fluid balance and is linked to multiple pathological conditions. Fluid moves through initial lymphatic networks into collecting vessels. Since initial lymphatics are not wrapped by smooth muscle cells, the mechanisms for fluid flow remain unclear. The objective of this study was to estimate the pressure drop needed for lymph flow through an intact initial lymphatic network. Pressure drops were computed for idealized networks with varying branch orders assuming Newtonian flow (1.5 cp viscosity). Vessel geometries per branch order were based on measurements from adult Wistar rat mesenteric microvascular networks. Network output velocity was equal to in vivo values reported for flow through a mesenteric collecting vessel. For vessel diameters = 50 mm and output velocity = 4 mm/s, the required pressure drop was approximately ‐1.12 mmHg. For diameters = 30 mm and velocity = 2 mm/s, the required pressure drop was approximately ‐1.55 mmHg. Our results suggest that suction pressures in collecting lymphatic vessels due to contraction and relaxation might be sufficient for drainage of proximal multi‐branched initial lymphatic networks without additional extrinsic forces.