Chylomicron biosynthesis plays a vital role in supplying essential lipids and lipid soluble vitamins to peripheral tissues for various functions. Despite this, the intracellular synthesis, trafficking, and secretion of chylomicrons remains only partly understood. The purpose of this review is to summarize the role of established proteins in this process and bring attention to recently identified proteins to provide an up-to-date model of chylomicron biosynthesis.

Recently, several proteins have been shown to play a role in the initial formation and lipidation of chylomicrons at the endoplasmic reticulum (ER), which include: TM6SF2, PLA2G12B, PRAP1, and SURF4. In addition, mitochondria have been implicated in chylomicron metabolism, but mechanistic insight is missing. The trafficking of chylomicrons from the ER to the Golgi, and the subsequent trafficking from the Golgi to the basolateral side of enterocytes, however, remains a mystery.

Progress in the chylomicron biosynthesis field is largely associated with findings in VLDL biosynthesis. In addition, increased insight in events after prechylomicrons leave the ER is needed. Given the important role of chylomicron biosynthesis in whole-body lipid metabolism, further research into the molecular mechanisms is warranted.

Lipoproteins are endogenous nanoparticles with essential roles in lipid transport and inflammation. Lipoproteins are also valuable in diagnosing and treating disease. For instance, certain lipoproteins are overexpressed in patients with atherosclerotic cardiovascular disease, and reconstituted lipoproteins have been extensively used for drug delivery. Radiolabeling has proven an especially powerful approach for studying and therapeutically exploiting lipoproteins. This review details how radiochemistry and nuclear imaging can facilitate the study of lipoproteins in health and disease. Among other topics, we discuss approaches for radiolabeling lipoproteins and detail how these have helped advance our understanding of lipoprotein biology and the diagnosis and treatment of diseases, including atherosclerosis, cancer, and hypercholesteremia.

We performed an extensive literature search on all peer-reviewed studies involving radiolabeled lipoproteins and selected representative examples to provide a high-level overview of the most important discoveries and technological advancements.

More than 200 peer-reviewed papers involved radiolabeled lipoproteins, spanning mechanistic, diagnostic, and therapeutic studies across a wide range of diseases.

Radiolabeling has been critical in advancing our understanding of lipoprotein biology and leveraging these nanomaterials for diagnosing and treating disease.

Intestinal lymphatic absorption is a crucial alternative to portal uptake for highly lipophilic drugs (log P > 5), bypassing first-pass metabolism. Unlike the portal-hepatic pathway, lymphatic uptake is rarely considered in physiologically based pharmacokinetic (PBPK) models for oral delivery. Our study developed an innovative Gastro-Intestinal (GI)-lymph-PBPK model that includes GI absorption, chylomicron extraction (CE) to rescue drugs from gut extraction (GE), and bypass hepatic extraction (HE). This model introduces CE clearance (CLCE), competing with GE clearance, to estimate the drug proportion subjected to CE versus GE. PBPK analysis for Buprenorphine revealed extensive GE (0.87) and HE (0.58), explaining the low bioavailability (F%) of 5.28% in rats. Buprenorphine prodrugs activated CLCE, leading to CE ranging from 0.37 to 0.79, boosting oral F% to 39.9%-79.9% in rats. To translate from rat to human, our model considered species differences in GI transit time, formulation, food-dependent drug dissolution, allometric scaling in CLCE, and between species variability in gut metabolism. Using Halofantrine, we established an allometric scaling factor for CLCE at 1.1. Accounting for six times faster human gut metabolism, our model predicted an extremely low oral F% of 0.382% for Buprenorphine in humans. Incorporating the allometric scaled CLCE competing with the extensive gut metabolism, our model predicted Buprenorphine prodrugs remains effective in enabling substantial absorption boosts, with oral F% estimates ranging from 15.8% to 56.7% in humans. This study highlights the significant potential of GI-lymph-PBPK modeling in predicting intestinal lymphatic absorption and facilitating cross-species translation.

Atherosclerosis (AS) is a serious disease that poses a significant threat to the global population. In this review, we analyze the development of AS from multiple perspectives, aiming to elucidate its molecular mechanisms. We also focus on imaging techniques and therapeutic approaches, highlighting the crucial role of nanomaterials in both imaging and therapy for AS. By leveraging their compatibility and targeting capabilities, nanomaterials can be integrated with traditional medical imaging and therapeutic agents to achieve targeted drug delivery, controlled release, and precise localization and imaging of atherosclerotic plaques.

The lymphatic system plays a central role in lipid absorption, which transports chylomicrons from the small intestine to the circulation. However, the molecular mechanism by which chylomicrons get into the intestinal lymphatics is unknown. Here we demonstrated that GPR182, a receptor in lymphatic endothelial cells (LECs), mediates dietary fat absorption. GPR182 knockout mice are resistant to dietary-induced obesity. GPR182 ablation in mice leads to poor lipid absorption and thereby a delay in growth during development. GPR182 binds and endocytoses lipoproteins broadly. Mechanistically, loss of GPR182 prevents chylomicrons from entering the lacteal lumen of the small intestine. GPR182 blockage with a monoclonal antibody (mAb) protects mice from dietary induced obesity. Together, our study identifies GPR182 as a lipoprotein receptor that mediates dietary fat absorption.

The lymphatic system plays an important role in health and many diseases, such as cancer, autoimmune, cardiovascular, metabolic, hepatic, viral, and other infectious diseases. The lymphatic system is, therefore, an important treatment target site for a range of diseases. Lymph nodes (LNs), rich in T cells, B cells, dendritic cells, and macrophages, are also primary sites of action for vaccines and immunotherapies. Promoting the delivery of therapeutics and vaccines to LNs can, therefore, enhance treatment efficacy and facilitate avoidance of off-target side effects by enabling a reduction in therapeutic dose. Several nanoparticle (NP) based delivery systems, such as polymeric NPs, lipid NPs, liposomes, micelles, and dendrimers, have been reported to enhance the delivery of therapeutics and/or vaccines to LNs. Specific uptake into the lymph following injection into tissues is highly dependent on particle properties, particularly particle size, as small molecules are more likely to be taken up by blood capillaries due to higher blood flow rates, whereas larger molecules and NPs can be specifically transported via the lymphatic vessels to LNs as the initial lymphatic capillaries are more permeable than blood capillaries. Once NPs enter LNs, particle properties also have an important influence on their disposition within the node and association with immune cells, which has significant implications for the design of vaccines and immunotherapies. This review article focuses on the impact of NP properties, such as size, surface charge and modification, and route of administration, on lymphatic uptake, retention, and interactions with immune cells in LNs. We suggest that optimizing all these factors can enhance the efficacy of vaccines or therapeutics with targets in the lymphatics and also be helpful for the rational design of vaccines. STATEMENT OF SIGNIFICANCE: The lymphatic system plays an essential role in health and is an important treatment target site for a range of diseases. Promoting the delivery of immunotherapies and vaccines to immune cells in lymph nodes can enhance efficacy and facilitate avoidance of off-target side effects by enabling a reduction in therapeutic dose. One of the major approaches used to deliver therapeutics and vaccines to lymph nodes is via injection in nanoparticle delivery systems. This review aims to provide an overview of the impact of nanoparticle properties, such as size, surface charge, modification, and route of administration, on lymphatic uptake, lymph node retention, and interactions with immune cells in lymph nodes. This will inform the design of future improved nanoparticle systems for vaccines and immunotherapies.

Inflammatory bowel disease, particularly Crohn's disease (CD), has been linked to modifications in mesenteric adipose tissue (MAT) and the phenomenon known as "creeping fat" (CrF). The presence of CrF is believed to serve as a predictor for early clinical recurrence following surgical intervention in patients with CD. Notably, the incorporation of the mesentery during ileocolic resection for CD has been correlated with a decrease in surgical recurrence, indicating the significant role of MAT in the pathogenesis of CD. While numerous studies have indicated that dysbiosis of the gut microbiota is a critical factor in the development of CD, the functional implications of translocated microbiota within the MAT of CD patients remain ambiguous. This manuscript commentary discusses a recent basic research conducted by Wu et al. In their study, intestinal bacteria from individuals were transplanted into CD model mice, revealing that fecal microbiota transplantation (FMT) from healthy donors alleviated CD symptoms, whereas FMT from CD patients exacerbated these symptoms. Importantly, FMT was found to affect intestinal permeability, barrier function, and the levels of proinflammatory factors and adipokines. Collectively, these findings suggest that targeting MAT and CrF may hold therapeutic potential for patients with CD. However, the study did not evaluate the composition of the intestinal microbiota of the donors or the subsequent alterations in the gut microbiota. Overall, the gut microbiota plays a crucial role in the histopathology of CD, and thus, targeting MAT and CrF may represent a promising avenue for treatment in this patient population.

The lymphatic system is essential in maintaining skin health through coordinated immunological actions. This review explores the relationship between lymphatic function and skin health, as well as the impact of lymphatic dysfunction in the development and progression of inflammatory skin disorders. A systemic search was conducted in the Web of Science, Embase, and Ovid MEDLINE databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Included studies were peer-reviewed human or animal research published in English from 2014 to 2024, focusing on inflammatory skin disorders, including skin cancer, autoimmune skin diseases, and infectious skin diseases. A total of 1232 citations were identified, with 37 studies meeting the eligibility criteria after assessment and critical appraisal. The review's findings highlight the essential role of lymphatics in maintaining skin health, mitigating inflammatory, infectious, and skin cancer-related processes, and delaying the effects of skin aging. The mechanisms underlying lymphatic function in these processes are complex, with some aspects needing further investigation. However, the evidence indicates that a well-functioning skin lymphatic system, supported by various cytokines, aids in reducing the inflammatory state, reduces inflammation, alleviates lymphedema, and prevents lymphatic stasis, which can increase infection risk. Several studies demonstrated that restoring lymphatic function through improved neutrophil migration and cytokine responses reduces the spread of infectious diseases.

Peritoneal carcinomatosis (PC) is caused by metastasis of primary tumor cells from intra-abdominal organs to the peritoneal surface. Intraperitoneal (IP) chemotherapy allows close contact of high concentrations of therapeutic agents with cancer cells in the peritoneal cavity to prolong patient survival. However, conventional IP chemotherapy is prone to rapid elimination from the peritoneal cavity and lacks specificity towards cancer cells. To address these challenges, there is an imperative demand for exploiting novel drug delivery systems to enhance drug retention in the peritoneal cavity and target PC cells. Therefore, in this review, we first recapitulate the physiological structures and barriers associated with IP drug delivery, highlighting the in vivo fate of nanoparticles (NPs) after IP administration. Furthermore, the influence of physicochemical properties (particle size, charge, surface modification, and carrier composition) on the in vivo fate of NPs is discussed. Perspectives on the rational design of NPs for IP therapy and recent clinical progress are also provided.

Cholesterol metabolites, particularly oxidized forms known as oxysterols, play crucial roles in modulating immune and metabolic processes across various tissues. Concentrations of local cholesterol and its metabolites influence tissue-specific immune responses by shaping the metabolic and spatial organization of immune cells in barrier organs like the small intestine (SI) and lungs. We explore recent molecular and cellular evidence supporting the metabolic adaptation of innate and adaptive immune cells in the SI and lung, driven by cholesterol and cholesterol metabolites. Further research should unravel the detailed molecular mechanisms and spatiotemporal adaptations involving cholesterol metabolites in distinct mucosal tissues in homeostasis or infection. We posit that pharmacological interventions targeting the generation or sensing of cholesterol metabolites might be leveraged to enhance long-term immune protection in mucosal tissues or prevent autoinflammatory states.

Tumour metastasis is a crucial factor in determining clinically challenging tumours. In this respect, the lymphatic system may act as potential entry portals for tumour metastasis, whilst, clinical detection of tumour-infiltrated lymph nodes also indicates poorer prognosis and higher metastatic risk. Whether tumour cells gain ferroptosis resistance in lymph that make them exhibit a stronger propensity for lymphatic dissemination compared to hematogenous spread might be a breakthrough for elucidating lymph-associated tumour metastasis. This review discusses how the lymphatic system endows tumour cells with ferroptosis resistance character, which makes them more propensity for lymph node pre-metastasis and distant metastasis through lymphatic circulation. Comprehensively considering the distinct structure and property of lymph and the unique metabolic characteristics of tumours, all of the lymphatic vessels, intestinal lymph and lymph nodes collectively manipulate an intricate interaction with the hematogenous system and afford substances exchange with tumour cells and extracellular vesicles, upon which make a ferroptosis resistant microenvironment for subsequent metastasis in distant organs and lymph nodes.

Historically, the intestinal lymphatics were considered passive conduits for fluids, immune cells, dietary lipids, lipid soluble vitamins, and lipophilic drugs. Studies of intestinal lymphatic drug delivery in the late 20th century focused primarily on the drugs' physicochemical properties, especially high lipophilicity, that resulted in intestinal lymphatic transport. More recent discoveries have changed our traditional view by demonstrating that the lymphatics are active, plastic, and tissue-specific players in a range of biological and pathological processes, including within the intestine. These findings have, in turn, inspired exploration of lymph-specific therapies for a range of diseases, as well as the development of more sophisticated strategies to actively deliver drugs or vaccines to the intestinal lymph, including a range of nanotechnologies, lipid prodrugs, and lipid-conjugated materials that "hitchhike" onto lymphatic transport pathways. With the increasing development of novel therapeutics such as biologics, there has been interest in whether these therapeutics are absorbed and transported through intestinal lymph after oral administration. Here we review the current state of understanding of the anatomy and physiology of the gastrointestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. We summarize the current state-of-the-art approaches to deliver drugs and quantify their uptake into the intestinal lymphatic system. Finally, and excitingly, we discuss recent examples of significant pharmacokinetic and therapeutic benefits achieved via intestinal lymphatic drug delivery. We also propose approaches to advance the development and clinical application of intestinal lymphatic delivery strategies in the future. SIGNIFICANCE STATEMENT: This comprehensive review details the understanding of the anatomy and physiology of the intestinal lymphatic system in health and disease, with a focus on aspects relevant to drug delivery. It highlights current state-of-the-art approaches to deliver drugs to the intestinal lymphatics and the shift toward the use of these strategies to achieve pharmacokinetic and therapeutic benefits for patients.

The Sonic hedgehog (Shh) signaling pathway controls embryonic development and tissue homeostasis after birth. This requires regulated solubilization of dual-lipidated, firmly plasma membrane-associated Shh precursors from producing cells. Although it is firmly established that the resistance-nodulation-division transporter Dispatched (Disp) drives this process, it is less clear how lipidated Shh solubilization from the plasma membrane is achieved. We have previously shown that Disp promotes proteolytic solubilization of Shh from its lipidated terminal peptide anchors. This process, termed shedding, converts tightly membrane-associated hydrophobic Shh precursors into delipidated soluble proteins. We show here that Disp-mediated Shh shedding is modulated by a serum factor that we identify as high-density lipoprotein (HDL). In addition to serving as a soluble sink for free membrane cholesterol, HDLs also accept the cholesterol-modified Shh peptide from Disp. The cholesteroylated Shh peptide is necessary and sufficient for Disp-mediated transfer because artificially cholesteroylated mCherry associates with HDL in a Disp-dependent manner, whereas an N-palmitoylated Shh variant lacking C-cholesterol does not. Disp-mediated Shh transfer to HDL is completed by proteolytic processing of the palmitoylated N-terminal membrane anchor. In contrast to dual-processed soluble Shh with moderate bioactivity, HDL-associated N-processed Shh is highly bioactive. We propose that the purpose of generating different soluble forms of Shh from the dual-lipidated precursor is to tune cellular responses in a tissue-type and time-specific manner.

Consumption of a diet rich in saturated fat increases lipid absorption from the intestine, assembly into chylomicrons, and delivery to metabolic tissues via the lymphatic and circulatory systems. Accumulation of ceramide lipids, composed of sphingosine and a fatty acid, in metabolic tissues contributes to the pathogenesis of cardiovascular diseases, type 2 diabetes mellitus and cancer. Using a mesenteric lymph duct cannulated rat model, we showed that ceramides are generated by the intestine and assembled into chylomicrons, which are transported via the mesenteric lymphatic system. A lipidomic screen of intestinal-derived chylomicrons identified a diverse range of fatty acid, sphingolipid, and glycerolipid species that have not been previously detected in chylomicrons, including the metabolically deleterious C16:0 ceramide that increased in response to high-fat feeding in rats and human high-lipid meal replacement enteral feeding. In conclusion, high-fat feeding increases the export of intestinal-derived C16:0 ceramide in chylomicrons, identifying a potentially unknown mechanism through which ceramides are transported systemically to contribute to metabolic dysfunction.

Intestinal lymphangiectasia (IL) is characterized by the dilation of intestinal lymphatic vessels, which can rupture and cause loss of lymph into the intestine. Due to the high content of proteins, lipoproteins, and lymphocytes in the intestinal lymph, loss of lymph might result in hypoproteinemia, hypoalbuminemia, hypogammaglobulinemia, and lymphocytopenia. In addition, there may be a depletion of minerals, lipids, and fat-soluble vitamins. IL can be primary due to inherent malfunctioning of the lymphatic system, or secondly, a result of various factors that may hinder lymphatic drainage either directly or indirectly. This condition has emerged as a subject of significant clinical interest. Given that the intestinal lymphatic system plays an important role in the body's fluid homeostasis, adaptive immunity, nutrient and drug absorption, intestinal transport, and systemic metabolism, its dysfunction may have wider implications. Although primary IL is rare, with varied clinical features, complications, treatment response, and outcomes, secondary IL is more common than previously believed. The definitive diagnosis of IL requires endoscopic demonstration of whitish villi (which frequently resemble snowflakes) and histological confirmation of dilated lacteals in the small intestinal mucosa. Treatment of IL is challenging and involves dietary modifications, managing underlying medical conditions, and using medications such as sirolimus and octreotide. Recognizing its prevalence and diverse etiology is crucial for targeted management of this challenging medical condition. This article provides a comprehensive exploration of the clinical implications associated with IL. In addition, it offers valuable insights into critical knowledge gaps in the existing diagnostic and management landscape.

The lymphatic vascular system spans nearly every organ in the body and serves as an important network that maintains fluid, metabolite, and immune cell homeostasis. Recently, there has been a growing interest in the role of lymphatic biology in chronic disorders outside the realm of lymphatic abnormalities, lymphedema, or oncology, such as cardiovascular-kidney-metabolic syndrome (CKM). We propose that enhancing lymphatic function pharmacologically may be a novel and effective way to improve quality of life in patients with CKM syndrome by engaging multiple pathologies at once throughout the body. Several promising therapeutic targets that enhance lymphatic function have already been reported and may have clinical benefit. However, much remains unclear of the discreet ways the lymphatic vasculature interacts with CKM pathogenesis, and translation of these therapeutic targets to clinical development is challenging. Thus, the field must improve characterization of lymphatic function in preclinical mouse models of CKM syndrome to better understand molecular mechanisms of disease and uncover effective therapies.

Delivery to peripheral lymphatics can be achieved following interstitial administration of nano-sized delivery systems (nanoparticles, liposomes, dendrimers etc) or molecules that hitchhike on endogenous nano-sized carriers (such as albumin). The published work concerning the hitchhiking approach has mostly focussed on the lymphatic uptake of vaccines conjugated directly to albumin binding moieties (ABMs such as lipids, Evans blue dye derivatives or peptides) and their subsequent trafficking into draining lymph nodes. The mechanisms underpinning access and transport of these constructs into lymph fluid, including potential interaction with other endogenous nanocarriers such as lipoproteins, have largely been ignored. Recently, we described a series of brush polyethylene glycol (PEG) polymers containing end terminal short-chain or medium-chain hydrocarbon tails (1C2 or 1C12, respectively), cholesterol moiety (Cho), or medium-chain or long-chain diacylglycerols (2C12 or 2C18, respectively). We evaluated the association of these materials with albumin and lipoprotein in rat plasma, and their intravenous (IV) and subcutaneous (SC) pharmacokinetic profiles. Here we fully detail the association of this suite of polymers with albumin and lipoproteins in rat lymph, which is expected to facilitate lymph transport of the materials from the SC injection site. Additionally, we characterise the thoracic lymph uptake, tissue and lymph node biodistribution of the lipidated brush PEG polymers following SC administration to thoracic lymph cannulated rats. All polymers had moderate lymphatic uptake in rats following SC dosing with the lymph uptake higher for 1C2-PEG, 2C12-PEG and 2C18-PEG (5.8%, 5.9% and 6.7% dose in lymph, respectively) compared with 1C12-PEG and Cho-PEG (both 1.5% dose in lymph). The enhanced lymph uptake of 1C2-PEG, 2C12-PEG and 2C18-PEG appeared related to their association profile with different lipoproteins. The five polymers displayed different biodistribution patterns in major organs and tissues in mice. All polymers reached immune cells deep within the inguinal lymph nodes of mice following SC dosing. The ability to access these immune cells suggests the potential of the polymers as platforms for the delivery of vaccines and immunotherapies. Future studies will focus on evaluating the lymphatic targeting and therapeutic potential of drug or vaccine-loaded polymers in pre-clinical disease models.

Lymph nodes are secondary lymphoid organs in which immune responses of the adaptive immune system are initiated and regulated. Distributed throughout the body and embedded in the lymphatic system, local lymph nodes are continuously informed about the state of the organs owing to a constant drainage of lymph. The tissue-derived lymph carries products of cell metabolism, proteins, carbohydrates, lipids, pathogens and circulating immune cells. Notably, there is a growing body of evidence that individual lymph nodes differ from each other in their capacity to generate immune responses. Here, we review the structure and function of the lymphatic system and then focus on the factors that lead to functional heterogeneity among different lymph nodes. We will discuss how lymph node heterogeneity impacts on cellular and humoral immune responses and the implications for vaccination, tumour development and tumour control by immunotherapy.

The entry of lipoproteins from blood into the arterial wall is a rate-limiting step in atherosclerosis. It is controversial whether this happens by filtration or regulated transendothelial transport.Because sphingosine-1-phosphate (S1P) preserves the endothelial barrier, we investigated in vivo and in vitro, whether S1P and its cognate S1P-receptor 3 (S1P3) regulate the transendothelial transport of lipoproteins.

Compared to apoE-haploinsufficient mice (CTRL), apoE-haploinsufficient mice with additional endothelium-specific knock-in of S1P3 (S1P3-iECKI) showed decreased transport of LDL and Evan's Blue but increased transport of HDL from blood into the peritoneal cave. After 30 weeks of high-fat diet feeding, S1P3-iECKI mice had lower levels of non-HDL-cholesterol and less atherosclerosis than CTRL mice. In vitro stimulation with an S1P3 agonist increased the transport of 125I-HDL but decreased the transport of 125I-LDL through human aortic endothelial cells (HAECs). Conversely, inhibition or knock-down of S1P3 decreased the transport of 125I-HDL but increased the transport of 125I-LDL. Silencing of SCARB1 encoding scavenger receptor B1 (SR-BI) abrogated the stimulation of 125I-HDL transport by the S1P3 agonist. The transendothelial transport of 125I-LDL was decreased by silencing of SCARB1 or ACVLR1 encoding activin-like kinase 1 but not by interference with LDLR. None of the three knock-downs prevented the stimulatory effect of S1P3 inhibition on transendothelial 125I-LDL transport.

S1P3 regulates the transendothelial transport of HDL and LDL oppositely by SR-BI-dependent and SR-BI-independent mechanisms, respectively. This divergence supports a contention that lipoproteins pass the endothelial barrier by specifically regulated mechanisms rather than passive filtration.

Chylous blood is the main cause of unqualified and scrapped blood among volunteer blood donors. Therefore, a diagnostic method that can quickly and accurately identify chylous blood before donation is needed. In this study, the GaiaSorter "Gaia" hyperspectral sorter was used to extract 254 bands of plasma images, ranging from 900 nm to 1700 nm. Four different machine learning algorithms were used, including decision tree, Gaussian Naive Bayes (GaussianNB), perceptron, and stochastic gradient descent models. First, the preliminary classification accuracies were compared with the original data, which showed that the effects of the decision tree and GaussianNB models were better; their average accuracies could reach over 90%. Then, the feature dimension reduction was performed on the original data. The results showed that the effects of the decision tree were better with a classification accuracy of 93.33%. the classification of chylous plasma using different chylous indices suggested that the accuracies of the decision trees model both before and after the feature dimension reductions were the best with over 80% accuracy. The results of feature dimension reduction showed that the characteristic bands corresponded to all kinds of plasma, thereby showing their classification and identification potential. By applying the spectral characteristics of plasma to medical technology, this study suggested a rapid and effective method for the identification of chylous plasma and provided a reference for the blood detection technology to achieve the goal of reducing wasting blood resources and improving the work efficiency of the medical staff.

Atherosclerosis results from the deposition and oxidation of LDL and immune cell infiltration in the sub-arterial space leading to arterial occlusion. Studies have shown that transcytosis transports circulating LDL across endothelial cells lining blood vessels. LDL transcytosis is initiated by binding to either scavenger receptor B1 (SR-B1) or activin A receptor-like kinase 1 on the apical side of endothelial cells leading to its transit and release on the basolateral side. HDL is thought to partly protect individuals from atherosclerosis due to its ability to remove excess cholesterol and act as an antioxidant. Apolipoprotein A1 (APOA1), an HDL constituent, can bind to SR-B1, raising the possibility that APOA1/HDL can compete with LDL for SR-B1 binding, thereby limiting LDL deposition in the sub-arterial space. To examine this possibility, we used in vitro approaches to quantify the internalization and transcytosis of fluorescent LDL in coronary endothelial cells. Using microscale thermophoresis and affinity capture, we find that SR-B1 and APOA1 interact and that binding is enhanced when using the cardioprotective variant of APOA1 termed Milano (APOA1-Milano). In male mice, transiently increasing the levels of HDL reduced the acute deposition of fluorescently labeled LDL in the atheroprone inner curvature of the aorta. Reduced LDL deposition was also observed when increasing circulating wild-type APOA1 or the APOA1-Milano variant, with a more robust inhibition from the APOA1-Milano. The results suggest that HDL may limit SR-B1-mediated LDL transcytosis and deposition, adding to the mechanisms by which it can act as an atheroprotective particle.

Cancer vaccines show huge potential for cancer prevention and treatment. However, their efficacy remains limited due to weak immunogenicity regarding inefficient stimulation of cytotoxic T lymphocyte (CTL) responses. Inspired by the unique characteristic and biological function of high-density lipoprotein (HDL), we here develop an HDL-mimicking nanovaccine with the commendable lymph-targeted capacity to potently elicit antitumor immunity using lipid nanoparticle that is co-loaded with specific cancer cytomembrane harboring a collection of tumor-associated antigens and an immune adjuvant. The nanoparticulate impact is explored on the efficiency of lymphatic targeting and dendritic cell uptake. The optimized nanovaccine promotes the co-delivery of antigens and adjuvants to lymph nodes and maintains antigen presentation of dendritic cells, resulting in long-term immune surveillance as the elevated frequency of CTLs within lymphoid organs and tumor tissue. Immunization of nanovaccine suppresses tumor formation and growth and augments the therapeutic efficacy of checkpoint inhibitors notably on the high-stemness melanoma in the mouse models.

This review focuses on the question of metabolic syndrome (MS) being a complex, but essentially monophyletic, galaxy of associated diseases/disorders, or just a syndrome of related but rather independent pathologies. The human nature of MS (its exceptionality in Nature and its close interdependence with human action and evolution) is presented and discussed. The text also describes the close interdependence of its components, with special emphasis on the description of their interrelations (including their syndromic development and recruitment), as well as their consequences upon energy handling and partition. The main theories on MS's origin and development are presented in relation to hepatic steatosis, type 2 diabetes, and obesity, but encompass most of the MS components described so far. The differential effects of sex and its biological consequences are considered under the light of human social needs and evolution, which are also directly related to MS epidemiology, severity, and relations with senescence. The triggering and maintenance factors of MS are discussed, with especial emphasis on inflammation, a complex process affecting different levels of organization and which is a critical element for MS development. Inflammation is also related to the operation of connective tissue (including the adipose organ) and the widely studied and acknowledged influence of diet. The role of diet composition, including the transcendence of the anaplerotic maintenance of the Krebs cycle from dietary amino acid supply (and its timing), is developed in the context of testosterone and β-estradiol control of the insulin-glycaemia hepatic core system of carbohydrate-triacylglycerol energy handling. The high probability of MS acting as a unique complex biological control system (essentially monophyletic) is presented, together with additional perspectives/considerations on the treatment of this 'very' human disease.

Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

Lymphatic vessels, comprising the secondary circulatory system in human body, play a multifaceted role in maintaining homeostasis among various tissues and organs. They are tasked with a serious of responsibilities, including the regulation of lymph absorption and transport, the orchestration of immune surveillance and responses. Lymphatic vessel development undergoes a series of sophisticated regulatory signaling pathways governing heterogeneous-origin cell populations stepwise to assemble into the highly specialized lymphatic vessel networks. Lymphangiogenesis, as defined by new lymphatic vessels sprouting from preexisting lymphatic vessels/embryonic veins, is the main developmental mechanism underlying the formation and expansion of lymphatic vessel networks in an embryo. However, abnormal lymphangiogenesis could be observed in many pathological conditions and has a close relationship with the development and progression of various diseases. Mechanistic studies have revealed a set of lymphangiogenic factors and cascades that may serve as the potential targets for regulating abnormal lymphangiogenesis, to further modulate the progression of diseases. Actually, an increasing number of clinical trials have demonstrated the promising interventions and showed the feasibility of currently available treatments for future clinical translation. Targeting lymphangiogenic promoters or inhibitors not only directly regulates abnormal lymphangiogenesis, but improves the efficacy of diverse treatments. In conclusion, we present a comprehensive overview of lymphatic vessel development and physiological functions, and describe the critical involvement of abnormal lymphangiogenesis in multiple diseases. Moreover, we summarize the targeting therapeutic values of abnormal lymphangiogenesis, providing novel perspectives for treatment strategy of multiple human diseases.

Although the phenomenon of hypertrophied adipose tissue surrounding inflamed bowel segments in Crohn's disease has been described since 1932, the mechanisms mediating the creeping fat formation and its role in the pathogenesis of the disease have not been fully unraveled. Recent advances demonstrating the multiple actions of adipose tissue beyond energy storage have brought creeping fat to the forefront of scientific research. In Crohn's disease, dysbiosis and transmural injury compromise the integrity of the intestinal barrier, resulting in an excessive influx of intraluminal microbiota and xenobiotics. The gut and peri-intestinal fat are in close anatomic relationship, implying a direct reciprocal immunologic relationship, whereas adipocytes are equipped with an arsenal of innate immunity sensors that respond to invading stimuli. As a result, adipocytes and their progenitor cells undergo profound immunophenotypic changes, leading to adipose tissue remodeling and eventual formation of creeping fat. Indeed, creeping fat is an immunologically active organ that synthesizes various pro- and anti-inflammatory cytokines, profibrotic mediators, and adipokines that serve as paracrine/autocrine signals and regulate immune responses. Therefore, creeping fat appears to be involved in inflammatory signaling, which explains why it has been associated with a higher severity or complicated phenotype of Crohn's disease. Interestingly, there is growing evidence for an alternative immunomodulatory function of creeping fat as a second barrier that prevents an abnormal systemic inflammatory response at the expense of an increasingly proliferating profibrotic environment. Further studies are needed to clarify how this modified adipose tissue exerts its antithetic effect during the course of Crohn's disease.

The lymphatic network is pivotal for various physiological functions in the human body. Accumulated evidence supports the role of therapeutic lymphangiogenesis in the treatment of several pathologies. Endogenous gasotransmitter, hydrogen sulfide (H2S) has been extensively studied for its potential as a pro-angiogenic factor and vascular function modulator. However, the role of H2S in governing lymphatic vessel formation, and underlying molecular mechanisms are understudied. The present study was designed to investigate the effects of H2S donor sodium hydrogen sulfide (NaHS) on lymphatic vascularization and pro-angiogenic signaling pathways using both in vitro and in vivo approaches. In vitro dose-response experiments showed increased proliferation and tube formation by NaHS-treated human lymphatic endothelial cells (LECs) compared with control cells. Immunoblotting performed with LEC lysates prepared after time-course NaHS treatment demonstrated increased activation of ERK1/2, AKT and eNOS after 20 min of NaHS stimulation. Further, NaHS treatment induced nitric oxide production, reduced reactive oxygen species generation, and promoted cell cycle in LECs. Additional cell cycle analysis showed that NaHS treatment abrogates oxidized LDL-induced cell cycle arrest in LECs. The results of in vivo Matrigel plug assay revealed increased lymphatic vessel density in Matrigel plugs containing NaHS compared with control plugs, however, no significant differences in angiogenesis and immune cell infiltration were observed. Collectively, these findings suggest that H2S donor NaHS promotes lymphatic vessel formation both in vitro and in vivo and may be utilized to promote reparative lymphangiogenesis to alleviate lymphatic dysfunction-related disorders.

Resolution of edema remains a significant clinical challenge. Conditions such as traumatic shock, sepsis, or diabetes often involve microvascular hyperpermeability, which leads to tissue and organ dysfunction. Lymphatic insufficiency due to genetic causes, surgical removal of lymph nodes, or infections, leads to varying degrees of tissue swelling that impair mobility and immune defenses. Treatment options are limited to management of edema as there are no specific therapeutics that have demonstrated significant success for ameliorating microvascular leakage or impaired lymphatic function. This review examines current knowledge about the physiological, cellular, and molecular mechanisms that control microvascular permeability and lymphatic clearance, the respective processes for interstitial fluid formation and removal. Clinical conditions featuring edema, along with potential future directions are discussed.

The ever-growing research on lymphatic biology has clearly identified lymphatic vessels as key players that maintain human health through their functional roles in tissue fluid homeostasis, immunosurveillance, lipid metabolism and inflammation. It is therefore not surprising that the list of human diseases associated with lymphatic malfunctions has grown larger, including issues beyond lymphedema, a pathology traditionally associated with lymphatic drainage insufficiency. Thus, the discovery of factors and pathways that can promote optimal lymphatic functions may offer new therapeutic options. Accumulating evidence indicates that aside from biochemical factors, biomechanical signals also regulate lymphatic vessel expansion and functions postnatally. Here, we review how mechanical forces induced by fluid shear stress affect the behavior and functions of lymphatic vessels and the mechanisms lymphatic vessels employ to sense and transduce these mechanical cues into biological signals.

The lymphatic system (LS) is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the LS has been shown to play a key role in the pathophysiology of many disease states. Thus, improved understanding of the anatomical and molecular characteristics of the LS may provide approaches for disease prevention or treatment. Recent advances harnessing single-cell technologies, clinical imaging, discovery of biomarkers, and computational tools have led to the development of strategies to study the LS. This Review summarizes the outcomes of the NIH workshop entitled "Yet to be Charted: Lymphatic System in Health and Disease," held in September 2022, with emphasis on major areas for advancement. International experts showcased the current state of knowledge regarding the LS and highlighted remaining challenges and opportunities to advance the field.

Lymphatic vessels are responsible for tissue drainage, and their malfunction is associated with chronic diseases. Lymph uptake occurs via specialized open cell-cell junctions between capillary lymphatic endothelial cells (LECs), whereas closed junctions in collecting LECs prevent lymph leakage. LEC junctions are known to dynamically remodel in development and disease, but how lymphatic permeability is regulated remains poorly understood.

We used various genetically engineered mouse models in combination with cellular, biochemical, and molecular biology approaches to elucidate the signaling pathways regulating junction morphology and function in lymphatic capillaries.

By studying the permeability of intestinal lacteal capillaries to lipoprotein particles known as chylomicrons, we show that ROCK (Rho-associated kinase)-dependent cytoskeletal contractility is a fundamental mechanism of LEC permeability regulation. We show that chylomicron-derived lipids trigger neonatal lacteal junction opening via ROCK-dependent contraction of junction-anchored stress fibers. LEC-specific ROCK deletion abolished junction opening and plasma lipid uptake. Chylomicrons additionally inhibited VEGF (vascular endothelial growth factor)-A signaling. We show that VEGF-A antagonizes LEC junction opening via VEGFR (VEGF receptor) 2 and VEGFR3-dependent PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) activation of the small GTPase RAC1 (Rac family small GTPase 1), thereby restricting RhoA (Ras homolog family member A)/ROCK-mediated cytoskeleton contraction.

Our results reveal that antagonistic inputs into ROCK-dependent cytoskeleton contractions regulate the interconversion of lymphatic junctions in the intestine and in other tissues, providing a tunable mechanism to control the lymphatic barrier.

The lymphatic vasculature provides an essential route to drain fluid, macromolecules, and immune cells from the interstitium as lymph, returning it to the bloodstream where the thoracic duct meets the subclavian vein. To ensure functional lymphatic drainage, the lymphatic system contains a complex network of vessels which has differential regulation of unique cell-cell junctions. The lymphatic endothelial cells lining initial lymphatic vessels form permeable "button-like" junctions which allow substances to enter the vessel. Collecting lymphatic vessels form less permeable "zipper-like" junctions which retain lymph within the vessel and prevent leakage. Therefore, sections of the lymphatic bed are differentially permeable, regulated in part by its junctional morphology. In this review, we will discuss our current understanding of regulating lymphatic junctional morphology, highlighting how it relates to lymphatic permeability during development and disease. We will also discuss the effect of alterations in lymphatic permeability on efficient lymphatic flux in health and how it may affect cardiovascular diseases, with a focus on atherosclerosis.

We conducted a retrospective multicentre study to investigate the association between acute pancreatitis, COVID-19, and pleural effusion. The study involved a total of 433 patients. Among them, 405 patients did not have COVID-19 infection, while 28 patients had both acute pancreatitis and COVID-19. Out of the 28 patients with both conditions, 12 also had pleural effusion. Among the 405 patients with acute pancreatitis without COVID-19, 48 had pleural effusion. The results showed that the relative risk of death associated with pleural effusion was approximately 4 times higher in patients with COVID-19 and pleural effusion compared to those with pleural effusion without COVID-19.

The lymphatics play important roles in chronic diseases/conditions that comprise the bulk of healthcare worldwide. Yet the ability to routinely image and diagnose lymphatic dysfunction, using commonly available clinical imaging modalities, has been lacking and as a result, the development of effective treatment strategies suffers. Nearly two decades ago, investigational near-infrared fluorescence lymphatic imaging and ICG lymphography were developed as routine diagnostic for clinically evaluating, quantifying, and treating lymphatic dysfunction in cancer-related and primary lymphedema, chronic venous disease, and more recently, autoimmune and neurodegenerative disorders. In this review, we provide an overview of what these non-invasive technologies have taught us about lymphatic (dys) function and anatomy in human studies and in corollary animal studies of human disease. We summarize by commenting on new impactful clinical frontiers in lymphatic science that remain to be facilitated by imaging.

Immunoglobulin A (IgA) secretion by plasma cells, terminally differentiated B cells residing in the intestinal lamina propria, assures microbiome homeostasis and protects the host against enteric infections. Exposure to diet-derived and commensal-derived signals provides immune cells with organizing cues that instruct their effector function and dynamically shape intestinal immune responses at the mucosal barrier. Recent data have described metabolic and microbial inputs controlling T cell and innate lymphoid cell activation in the gut; however, whether IgA-secreting lamina propria plasma cells are tuned by local stimuli is completely unknown. Although antibody secretion is considered to be imprinted during B cell differentiation and therefore largely unaffected by environmental changes, a rapid modulation of IgA levels in response to intestinal fluctuations might be beneficial to the host. In the present study, we showed that dietary cholesterol absorption and commensal recognition by duodenal intestinal epithelial cells lead to the production of oxysterols, evolutionarily conserved lipids with immunomodulatory functions. Using conditional cholesterol 25-hydroxylase deleter mouse line we demonstrated that 7α,25-dihydroxycholesterol from epithelial cells is critical to restrain IgA secretion against commensal- and pathogen-derived antigens in the gut. Intestinal plasma cells sense oxysterols via the chemoattractant receptor GPR183 and couple their tissue positioning with IgA secretion. Our findings revealed a new mechanism linking dietary cholesterol and humoral immune responses centered around plasma cell localization for efficient mucosal protection.

Background: Fluids, solutes and immune cells have been demonstrated to drain from the brain and surrounding structures to the cervical lymph vessels and nodes in the neck via meningeal lymphatics, nasal lymphatics and/or lymphatic vessels associated with cranial nerves. A method to cannulate the efferent cervical lymph duct for continuous cervical lymph fluid collection in rodents has not been described previously and would assist in evaluating the transport of molecules and immune cells from the head and brain via the lymphatics, as well as changes in lymphatic transport and lymph composition with different physiological challenges or diseases. Aim: To develop a novel method to cannulate and continuously collect lymph fluid from the cervical lymph duct in rats and to analyze the protein, lipid and immune cell composition of the collected cervical lymph fluid. Methods: Male Sprague-Dawley rats were cannulated at the carotid artery with or without cannulation or ligation at the cervical lymph duct. Samples of blood, whole lymph and isolated lipoprotein fractions of lymph were collected and analyzed for lipid and protein composition using commercial kits. Whole lymph samples were centrifuged and isolated pellets were stained and processed for flow cytometry analysis of CD3⁺, CD4⁺, CD8a⁺, CD45R⁺ (B220) and viable cell populations. Results: Flow rate, phospholipid, triglyceride, cholesterol ester, free cholesterol and protein concentrations in cervical lymph were 0.094 ± 0.014 mL/h, 0.34 ± 0.10, 0.30 ± 0.04, 0.07 ± 0.02, 0.02 ± 0.01 and 16.78 ± 2.06 mg/mL, respectively. Protein was mostly contained within the non-lipoprotein fraction but all lipoprotein types were also present. Flow cytometry analysis of cervical lymph showed that 67.1 ± 7.4% of cells were CD3⁺/CD4⁺ T lymphocytes, 5.8 ± 1.6% of cells were CD3⁺/CD8⁺ T lymphocytes, and 10.8 ± 4.6% of cells were CD3^-/CD45R⁺ B lymphocytes. The remaining 16.3 ± 4.6% cells were CD3^-/CD45^- and identified as non-lymphocytes. Conclusion: Our novel cervical lymph cannulation method enables quantitative analysis of the lymphatic transport of immune cells and molecules in the cervical lymph of rats for the first time. This valuable tool will enable more detailed quantitative analysis of changes to cervical lymph composition and transport in health and disease, and could be a valuable resource for discovery of biomarkers or therapeutic targets in future studies.

Mast cells (MCs), are hematopoetically-derived secretory immune cells that release preformed as well as de novo synthesized inflammatory mediators in response to activation by several stimuli. Based on their role in inflammatory responses, particularly in the lung and skin, MCs provide an effective target for anti-inflammatory therapeutic strategies. Drug-delivery of lipophilic payloads to MCs can be challenging due to their functionally distinct intracellular structures. In the present study, pH-sensitive cationic lipid-based nanoparticles (LNPs) composed of DODMA, DODAP or DOTAP lipids that encapsulated a GFP or eGFP plasmid were constructed using non-turbulent microfluidic mixing. This approach achieved up to 75-92% encapsulation efficiency. Dynamic light scattering revealed a uniformly sized and homogeneous dispersion of LNPs. To promote cellular internalization, LNPs were complexed with apolipoproteins, amphipathic proteins capable of binding lipids and facilitating their transport into cells. Cryo-TEM analysis showed that LNP structure was differentially modified when associated with different types of apolipoproteins. LNP preparations made up of DODMA or DODMA, DODAP and DOTAP lipids were coated with seven apolipoproteins (Apo A1, B, C3, D, E2, E4 and H). Differentiated bone-marrow derived mouse mast cells (BMMCs) were exposed to apolipoprotein-LNP and internalization was measured using flow cytometry. Out of all the apolipoproteins tested, ApoC3 most efficiently facilitated cellular internalization of the LNP into BMMCs as determined by GFP fluorescence using flow cytometry. These effects were confirmed in a less differentiated but also interleukin-3-dependent model of mouse mast cells, MC/9. ApoC3-LNP enhanced internalization by BMMC in a concentration-dependent manner and this was significantly increased when BMMC were pre-treated with inhibitors of actin polymerization, suggesting a dependence on intracellular shuttling. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) decreased ApoC3-LNP internalization and reduced the expression of apolipoprotein E receptor 2 (ApoER2), suggesting that ApoC3-LNP binding to ApoER2 may be responsible for its enhanced internalization. Furthermore, ApoC3 fails to facilitate internalization of LNPs in Lrp8^-/- KO BMMC that do not express ApoER2 on their cell surface. Altogether, our studies reveal an important role of ApoC3 in facilitating internalization of cationic LNPs into MCs.

Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and dietary lipid uptake and transport. Emerging research has indicated that the promotion of lymphatic vascular growth, remodeling, and function can reduce inflammation and diminish disease severity in several pathophysiologic conditions. In particular, recent groundbreaking studies have shown that lymphangiogenesis, which describes the formation of new lymphatic vessels from the existing lymphatic vasculature, can be beneficial for the alleviation and resolution of metabolic and cardiovascular diseases. Therefore, promoting lymphangiogenesis represents a promising therapeutic approach. This brief review summarizes the most recent findings related to the modulation of lymphatic function to treat metabolic and cardiovascular diseases such as obesity, myocardial infarction, atherosclerosis, and hypertension. We also discuss experimental and therapeutic approaches to enforce lymphatic growth and remodeling as well as efforts to define the molecular and cellular mechanisms underlying these processes.

The lymphatic system plays a significant role in homeostasis and drainage of excess fluid back into venous circulation. Lymphatics are also associated with a number of diseases including lymphedema, tumor metastasis, and various lymphatic malformations. Emerging evidence suggests that lymphatics might have a bigger connection to the blood vascular system than originally presumed. As these two systems are often studied in isolation, several knowledge gaps exist surrounding what constitutes lymphatic vascular plasticity, under what conditions it arises, and where structures characteristic of plasticity can form. The objective of this review is to overview current structural, cell lineage-based, and cell identity-based evidence for lymphatic plasticity. These examples of plasticity will then be considered in the context of potential clinical and surgical implications of this evolving research area. This review details our current understanding of lymphatic plasticity, highlights key unanswered questions in the field, and motivates future research aimed at clarifying the role and therapeutic potential of lymphatic plasticity in disease.

Creeping fat (CrF), also known as fat wrapping, is a significant disease characteristic of Crohn's disease (CD). The transmural inflammation impairs intestinal integrity and facilitates bacteria translocation, aggravating immune response. CrF is a rich source of pro-inflammatory and pro-fibrotic cytokines with complex immune microenvironment. The inflamed and stricturing intestine is often wrapped by CrF, and CrF is associated with greater severity of CD. The large amount of innate and adaptive immune cells as well as adipocytes in CrF promote fibrosis in the affected intestine by secreting large amount of pro-fibrotic cytokines, adipokines, growth factors and fatty acids. CrF is a potential therapeutic target for CD treatment and a promising bio-marker for predicting response to drug therapy. This review aims to summarize and update the clinical manifestation and application of CrF and the underlying molecular mechanism involved in the pathogenesis of intestinal inflammation and fibrosis in CD.

With excellent physicochemical properties, inorganic nanomaterials (INMs) have exhibited a series of attractive applications in biomedical fields. Biological barriers prevent successful delivery of nanomedicine in living systems that limits the development of nanomedicine especially for sufficient delivery of drugs and effective therapy. Numerous researches have focused on overcoming these biological barriers and homogeneity of organisms to enhance therapeutic efficacy, however, most of these strategies fail to resolve these challenges. In this review, we present the latest progress about how INMs interact with biological barriers and penetrate these barriers. We also summarize that both native structure and components of biological barriers and physicochemical properties of INMs contributed to the penetration capacity. Knowledge about the relationship between INMs structure and penetration capacity will guide the design and application of functional and efficient nanomedicine in the future.

Lymphatic and blood microvascular networks play critical roles in the clearance of excess fluid from local tissue spaces. Given the importance of these dynamics in inflammation, tumor metastasis, and lymphedema, understanding the coordinated function and remodeling between lymphatic and blood vessels in adult tissues is necessary. Knowledge gaps exist because the functions of these two systems are typically considered separately. The objective of this review was to highlight the coordinated functional relationships between blood and lymphatic vessels in adult microvascular networks. Structural, functional, temporal, and spatial relationships will be framed in the context of maintaining tissue homeostasis, vessel permeability, and system remodeling. The integration across systems will emphasize the influence of the local environment on cellular and molecular dynamics involved in fluid flow from blood capillaries to initial lymphatic vessels in microvascular networks.