Aqueous humor as eye lymph: A crossroad between venous and lymphatic system.

Aqueous humor (AQH) is a transparent fluid with characteristics similar to those of the interstitial fluid, which fills the eyeball posterior and anterior chambers and circulates in them from the sites of production to those of drainage. The AQH volume and pressure homeostasis is essential for the trophism of the ocular avascular tissues and their normal structure and function. Different AQH outflow pathways exist, including a main pathway, quite well defined anatomically and referred to as the conventional pathway, and some accessory pathways, more recently described and still not fully morphofunctionally understood, generically referred to as unconventional pathways. The conventional pathway is based on the existence of a series of conduits starting with the trabecular meshwork and Schlemm's Canal and continuing with a system of intrascleral and episcleral venules, which are tributaries to veins of the anterior segment of the eyeball. The unconventional pathways are mainly represented by the uveoscleral pathway, in which AQH flows through clefts, interstitial conduits located in the ciliary body and sclera, and then merges into the aforementioned intrascleral and episcleral venules. A further unconventional pathway, the lymphatic pathway, has been supported by the demonstration of lymphatic microvessels in the limbal sclera and, possibly, in the uvea (ciliary body, choroid) as well as by the ocular glymphatic channels, present in the neural retina and optic nerve. It follows that AQH may be drained from the eyeball through blood vessels (TM-SC pathway, US pathway) or lymphatic vessels (lymphatic pathway), and the different pathways may integrate or compensate for each other, optimizing the AQH drainage. The present review aims to define the state-of-the-art concerning the structural organization and the functional anatomy of all the AQH outflow pathways. Particular attention is paid to examining the regulatory mechanisms active in each of them. The new data on the anatomy and physiology of AQH outflow pathways is the key to understanding the pathophysiology of AQH outflow disorders and could open the way for novel approaches to their treatment.

Spatial Organization of the Transport of Interstitial Fluid and Lymph in Rat Liver (Scanning Electron Microscopy of Injection Replicas).

Using the method of scanning electron microscopy of injection replicas, we studied the movement of a new injection mass between the blood microcirculation system, interstitial space, lymphatic system, and bile transport system in rat liver under normal conditions and 3 days after the occlusion of the common bile duct. The casts of the perisinusoidal spaces of Disse's after injection of the injection mass through the portal vein and common bile duct were obtained. Their direct transition not only in "leakages" structurally related to lymphatic capillaries in interlobular spaces, but also in perivascular spaces around the portal and hepatic veins. The flow of the injection mass through the perivascular spaces leads to the formation of peculiar "sheaths" around hepatic veins and components of the portal complex. The proposed approach allows effective visualization of the structural basis of interaction of various compartments of the fluid microcirculation in the liver under normal and pathological conditions.

Innominate Vein Turn-down Procedure for Failing Fontan Circulation.

After the Fontan, systemic venous hypertension induces pathophysiologic changes in the lymphatic system that can result in complications of pleural effusion, ascites, plastic bronchitis, and protein losing enteropathy. Advances in medical therapy and novel interventional approaches have not substantially improved the poor prognosis of these complications. A more physiological approach has been developed by decompression of the thoracic duct to the lower pressure common atrium with a concomitant increase of preload. Diverting the innominate vein to the common atrium increases the transport capacity of the thoracic duct, which in most patients enters the circulation at the left subclavian-jugular vein junction. Contrary to the fenestrated Fontan circulation, in which the thoracic duct is drained into the high pressure Fontan circulation, turn down of the innominate vein to the common atrium effectively decompresses the thoracic duct to the lower pressure system with "diastolic suctioning" of lymph. Innominate vein turn-down may be considered for medical-refractory post-Fontan lymphatic complications of persistent chylothorax, plastic bronchitis, and protein losing enteropathy. Prophylactic innominate vein turn-down may also be considered at time of the Fontan operation for patients that are higher risk for lymphatic complications.

Lymphatic Circulation Disseminates Bartonella Infection Into Bloodstream.

The hallmark of Bartonella infection is long-lasting intraerythrocytic parasitism. However, the process of Bartonella bacteremia is still enigmatic. In the current study, we used Bartonella tribocorum to determine how Bartonella invasion into the bloodstream from dermal inoculation might occur. Bartonella was poorly phagocytized by peritoneal macrophages in vitro. Intracellular Bartonella survived and replicated in macrophages at an early stage of infection. Intracellular Bartonella inhibited spontaneous cell death of macrophages. They also inhibited Salmonella-induced pyroptosis and mildly reduced inflammasome activation through an unidentified mechanism. A rat model confirmed that Bartonella was also inadequately phagocytized in vivo, because numerous free-floating bacilli were observed in lymph collected from thoracic duct drainage as early as 2 hours after inoculation. Lymphatic fluid drainage in the bloodstream significantly reduced the bacterial load in the bloodstream. These findings illustrated a potential route by which Bartonella invade bloodstream from dermal inoculation before they are competent to infect erythrocytes.

Comparison of metabolic rates of ropivacaine in cerebrospinal fluid as inferred from plasma concentrations between elderly patients and young patients.

BACKGROUND: With the aging of human society, more and more elderly patients have to undergo surgery and anesthesia. Clinical observations have indicated from time to time that spinal anesthesia in the elderly appears to last longer than in young people, although there is limited research in this area and the mechanism is unclear at present time. This research work is expected to help understand the decline of local anesthetic metabolism in cerebrospinal fluid of elderly patients so as to help them with precise anesthesia and rapid rehabilitation. METHODS: Twenty patients with spinal anesthesia in orthopedic lower limb surgery were selected to study the rate of drug metabolism in cerebrospinal fluid in two age groups, i.e.,18-30 years old and 75-90 years old. Ropivacaine in peripheral blood is used as a probe to reflect the speed of drug metabolism in cerebrospinal fluid. The contents of total Aß protein and hyaluronic acid in the cerebrospinal fluid were investigated as well. RESULTS: The equivalent dose of ropivacaine anesthetizes the elderly group for a longer time. The metabolism rate of ropivacaine in an elderly patient was slower than that of a young patient. No significant difference in total Aß protein between the two groups was observed while hyaluronic acid in the elderly group was significantly higher than that in the young group. CONCLUSIONS: This study shows that the dose of ropivacaine should be reduced when used for anesthesia in elderly patients. The cumulation of ropivacaine and HA appears to imitate the degeneration of central lymphatic circulation metabolism in elderly people.

Platycodon grandiflorus polysaccharide regulates colonic immunity through mesenteric lymphatic circulation to attenuate ulcerative colitis.

Platycodon grandiflorus polysaccharide (PGP) is one of the main components of P. grandiflorus, but the mechanism of its anti-inflammatory effect has not been fully elucidated. The aim of this study was to evaluate the therapeutic effect of PGP on mice with dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) and explore the underlying mechanisms. The results showed that PGP treatment inhibited the weight loss of DSS-induced UC mice, increased colon length, and reduced DAI, spleen index, and pathological damage within the colon. PGP also reduced the levels of pro-inflammatory cytokines and inhibited the enhancement of oxidative stress and MPO activity. Meanwhile, PGP restored the levels of Th1, Th2, Th17, and Treg cell-related cytokines and transcription factors in the colon to regulate colonic immunity. Further studies revealed that PGP regulated the balance of colonic immune cells through mesenteric lymphatic circulation. Taken together, PGP exerts anti-inflammatory and anti-oxidant effect and regulates colonic immunity to attenuate DSS-induced UC through mesenteric lymphatic circulation.

Porphyromonas gingivalis regulates atherosclerosis through an immune pathway.

Atherosclerosis (AS) is a chronic inflammatory disease, involving a pathological process of endothelial dysfunction, lipid deposition, plaque rupture, and arterial occlusion, and is one of the leading causes of death in the world population. The progression of AS is closely associated with several inflammatory diseases, among which periodontitis has been shown to increase the risk of AS. Porphyromonas gingivalis (P. gingivalis), presenting in large numbers in subgingival plaque biofilms, is the "dominant flora" in periodontitis, and its multiple virulence factors are important in stimulating host immunity. Therefore, it is significant to elucidate the potential mechanism and association between P. gingivalis and AS to prevent and treat AS. By summarizing the existing studies, we found that P. gingivalis promotes the progression of AS through multiple immune pathways. P. gingivalis can escape host immune clearance and, in various forms, circulate with blood and lymph and colonize arterial vessel walls, directly inducing local inflammation in blood vessels. It also induces the production of systemic inflammatory mediators and autoimmune antibodies, disrupts the serum lipid profile, and thus promotes the progression of AS. In this paper, we summarize the recent evidence (including clinical studies and animal studies) on the correlation between P. gingivalis and AS, and describe the specific immune mechanisms by which P. gingivalis promotes AS progression from three aspects (immune escape, blood circulation, and lymphatic circulation), providing new insights into the prevention and treatment of AS by suppressing periodontal pathogenic bacteria.

In situ rearranged multifunctional lipid nanoparticles via synergistic potentiation for oral insulin delivery.

Oral administration of therapeutic peptides/proteins (TPPs) is confronted with multiple gastrointestinal (GI) barriers such as mucus and intestinal epithelium, and the first-pass metabolism in the liver is also responsible for low bioavailability. In situ rearranged multifunctional lipid nanoparticles (LNs) were developed to overcome these obstacles via synergistic potentiation for oral insulin delivery. After the reverse micelles of insulin (RMI) containing functional components were gavaged, LNs formed in situ under the hydration effect of GI fluid. The nearly electroneutral surface generated by the rearrangement of sodium deoxycholate (SDC) and chitosan (CS) on the reverse micelle core facilitated LNs (RMI@SDC@SB12-CS) to overcome mucus barrier and the sulfobetaine 12 (SB12) modification further promoted epithelial uptake of LNs. Subsequently, chylomicron-like particles formed by the lipid core in the intestinal epithelium were easily transported to the lymphatic circulation and then into the systemic circulation, thus avoiding hepatic first-pass metabolism. Eventually, RMI@SDC@SB12-CS achieved a high pharmacological bioavailability of 13.7% in diabetic rats. In conclusion, this study provides a versatile platform for enhanced oral insulin delivery.

Reelin through the years: From brain development to inflammation.

Reelin was originally identified as a regulator of neuronal migration and synaptic function, but its non-neuronal functions have received far less attention. Reelin participates in organ development and physiological functions in various tissues, but it is also dysregulated in some diseases. In the cardiovascular system, Reelin is abundant in the blood, where it contributes to platelet adhesion and coagulation, as well as vascular adhesion and permeability of leukocytes. It is a pro-inflammatory and pro-thrombotic factor with important implications for autoinflammatory and autoimmune diseases such as multiple sclerosis, Alzheimer's disease, arthritis, atherosclerosis, or cancer. Mechanistically, Reelin is a large secreted glycoprotein that binds to several membrane receptors, including ApoER2, VLDLR, integrins, and ephrins. Reelin signaling depends on the cell type but mostly involves phosphorylation of NF-κB, PI3K, AKT, or JAK/STAT. This review focuses on non-neuronal functions and the therapeutic potential of Reelin, while highlighting secretion, signaling, and functional similarities between cell types.

Host-guest interactions of indocyanine green with ß-cyclodextrin permit real-time characterization of the rat lymphatic system.

Objective: Fluorescence contrast technology using indocyanine green (ICG) could be useful for the rapid, dynamic, and objective assessment of blood vessels and the surrounding tissues when combined with near-infrared (NIR) imaging. Although ICG is a clinically available NIR fluorescence imaging probe, it can easily aggregate and is, thus, unstable. In the present study, we examined the efficacy of a host-guest ICG-ß-cyclodextrin (CD) complex, which is used in pharmaceutics to improve the water solubility, stability, and bioavailability of hydrophobic molecules, for NIR imaging after hind footpad administration in a rat model. Methods: To verify the performance of the ICG-ß-CD complex with the host-guest self-assembly method in vivo, we performed simultaneous small animal (IVIS Spectrum system; PerkinElmer, Waltham, MA) and clinical (DIGI-MIH-001 near-infrared fluorescence imaging system; Beijing Digital Precision Medical Technology Co, Ltd, Beijing, China) imaging and evaluated the fluorescent properties of the ICG-ß-CD complex in the hind footpad model of Sprague-Dawley male rats. Results: We successfully prepared the ICG-ß-CD complex. Compared with ICG, in vivo experiments showed that this complex had reduced absorbance at 710 nm and increased absorbance at 780 nm, indicating that it could prevent the dimeric aggregation of ICG, and a significantly higher fluorescence intensity at 730 nm excitation. After injection of 1.25 mg/mL of ICG or ICG-ß-CD complex solutions into the rat hind footpad, fluorescent NIR lymphatic images were observed with both imaging systems. During the 12-hour observation period, the signal background ratio of ICG-ß-CD showed a greater acute increase and a higher signal background ratio compared with ICG. The signal background ratio of ICG-ß-CD was 125 to 100 from 260 to 540 minutes. These in vivo data suggest that ICG-ß-CD has greater diffusion from the injection site and faster transport to the lymphatic system compared with ICG. Conclusions: ICG-ß-CD showed faster lymphatic transport than ICG, allowing for more rapid lymphatic NIR imaging. Thus, the ICG-ß-CD complex might be a promising fluorescent agent for clinical lymphatic NIR imaging.

Research Progress on Intracranial Lymphatic Circulation and Its Involvement in Disorders.

The lymphatic system is an important part of the circulatory system, as an auxiliary system of the vein, which has the functions of immune defense, maintaining the stability of the internal environment, and regulating the pressure of the tissue. It has long been thought that there are no typical lymphatic vessels consisting of endothelial cells in the central nervous system (CNS). In recent years, studies have confirmed the presence of lymphatic vessels lined with endothelial cells in the meninges. The periventricular meninges of the CNS host different populations of immune cells that affect the immune response associated with the CNS, and the continuous drainage of interstitial and cerebrospinal fluid produced in the CNS also proceeds mainly by the lymphatic system. This fluid process mobilizes to a large extent the transfer of antigens produced by the CNS to the meningeal immune cells and subsequently to the peripheral immune system through the lymphatic network, with clinically important implications for infectious diseases, autoimmunity, and tumor immunology. In our review, we discussed recent research advances in intracranial lymphatic circulation and the pathogenesis of its associated diseases, especially the discovery of meningeal lymphatic vessels, which has led to new therapeutic targets for the treatment of diseases associated with the intracranial lymphatic system.

Anatomic evidence shows that lymphatic drainage exists in the pituitary to loop the cerebral lymphatic circulation.

Respiratory infections can result in intracranial infections and unknown neurological symptoms. The central nervous system lacks classical meningeal lymphatic (circulation) drainage, and the exact underlying mechanisms of how immune cells from the peripheral lymphatic system enter the central nervous system (CNS) remain unknown. To determine whether the perinasal lymphatic system or lymphatic vessels are involved in cerebral immune defence and play a role in causing CNS infections (especially respiratory tract-related infections), we performed an anatomic study to investigate the drainage differences between the perinasal and intracerebral lymphatic systems by using injection of Evans blue and anatomic surgery, together with immunohistochemistry and immunofluorescence assays. Surprisingly, we found that (1) the pituitary (adenohypophysis) is involved and is rich in lymphatic vessels and (2) perinasal tissue could communicate with central pituitary lymphatic vessels in a specific and unidirectional manner. Taken together, our study may be the first to anatomically demonstrate the existence of novel lymphatic vessel structures in the pituitary, as well as their communication with the perinasal (lymphatic) tissue. Our findings suggest the existence of an ultimate loop for "classical" meningeal lymphatic drainage and are relevant to cerebral infection and immune defence.

Proprioceptive neuromuscular facilitation in the functionality and lymphatic circulation of the upper limb of women undergoing breast cancer treatment.

BACKGROUND: With the increase in survival of women treated for breast cancer, it is necessary to evaluate the effect of therapeutic resources on co-morbidities resulting from the surgical treatment of the disease. The aim of this study was to evaluate the effects of proprioceptive neuromuscular facilitation on the functionality and lymphatic circulation of the upper limb involved in the treatment of breast cancer. METHODS: The study was conducted according to randomized clinical trial design. Thirty-two women at a mean age of 52.20 (±8.32) years, submitted to breast cancer treatment, divided into two groups, control - women submitted to standard breast cancer treatment, and treated group, composed of women who underwent breast cancer treatment and rehabilitation with the proprioceptive neuromuscular facilitation technique. Palmar grip strength with dynamometer and shoulder range of motion with goniometer were evaluated. Lymphatic circulation analysis was performed in a computerized scintillation chamber, before and after therapeutic intervention. FINDINGS: In the results obtained, a significant increase (p < 0.05) of palmar grip strength was observed, a significant increase in range of motion of flexion (p < 0.001), extension (p < 0.0012), abduction (p < 0.0001), external rotation (p < 0.0001), internal rotation (p < 0.0001), and not significant for lymphatic flow (p > 0.05). INTERPRETATION: The results obtained in this study allow us to conclude that proprioceptive neuromuscular facilitation favors an increase in muscle strength, range of motion, but not in lymphatic flow, in women undergoing surgical treatment for breast cancer.

The Role of Interstitial Matrix and the Lymphatic System in Gastrointestinal Lipid and Lipoprotein Metabolism.

This review emphasizes the events that take place after the chylomicrons are secreted by the enterocytes through exocytosis. First, we will discuss the journey of how chylomicrons cross the basement membrane to enter the lamina propria. Then the chylomicrons have to travel across the lamina propria before they can enter the lacteals. To understand the factors affecting the trafficking of chylomicron particles across the lamina propria, it is important to understand the composition and properties of the lamina propria. With different degree of hydration, the pores of the lamina propria (sponge) changes. The greater the hydration, the greater the pore size and thus the easier the diffusion of the chylomicron particles across the lamina propria to enter the lacteals. The mechanism of the entry of lacteals is discussed in considerable details. We and others have demonstrated that intestinal fat absorption, but not the absorption of protein or carbohydrates, activates the intestinal mucosal mast cells to release many products including mucosal mast cell protease II in the rat. The activation of intestinal mucosal mast cells by fat absorption involves the process of chylomicron formation since the absorption of both medium and short-chain fatty acids do not activate the mast cells. Fat absorption has been associated with increased intestinal permeability. We hypothesize that there is a link between fat absorption, activation of mucosal mast cells, and the leaky gut phenomenon (increased intestinal permeability). Microbiome may also be involved in this chain of events associated with fat absorption. This review is presented in sequence under the following headings: (1) Introduction; (2) Structure and properties of the gut epithelial basement membrane; (3) Composition and physical properties of the interstitial matrix of the lamina propria; (4) The movement of chylomicrons across the interstitial matrix of the lamina propria and importance of the hydration of the interstitial matrix of the lamina propria and the movement of chylomicrons; (5) Entry of the chylomicrons into the intestinal lacteals; (6) Activation of mucosal mast cells by fat absorption and the metabolic consequences; and (7) Link between chylomicron transport, mucosal mast cell activation, leaky gut, and the microbiome.

The Lymphatic Fluid.

This review will highlight our current understanding of the formation, circulation, and immunological role of lymphatic fluid. The formation of the extracellular fluid depends on the net balance between the hydrostatic and osmotic pressure gradients effective in the capillary beds. Lymph originates from the extracellular fluid and its composition combines the ultrafiltrated plasma proteins with the proteome generated by the metabolic activities of each parenchymal tissue. Several analyses have indicated how the lymph composition reflects the organs' physiological and pathological states. The collected lymphatic fluid moves from the capillaries into progressively larger collectors toward the draining lymph node aided by the lymphangion contractility and unidirectional valves, which prevent backflow. The proteomic composition of the lymphatic fluid is reflected in the MHC II peptidome presented by nodal antigen-presenting cells. Taken together, the past few years have generated new interest in the formation, transport, and immunological role of the lymphatic fluid.