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Background: Crohn's disease (CD) is a chronic inflammatory disease in the intestinal tract. Mesenteric fat wrapping and thickening, or creeping fat (CrF), is a typical characteristic of CD and it involves lymphangiogenesis and altered lymphatic function. By releasing extracellular vesicles (EVs), adipose tissue‐derived stem cells (ADSCs) can regulate their adjacent cells. However, the regulating roles of ADSC‐EVs in CrF (CrF‐EVs) in CD, especially in modulating lymphatic function and mitigating the progression of mesenteritis and colitis, remains elusive. Methods: To evaluate the regulative roles of CrF‐EVs on lymphatic functions, in vitro assays were performed using human lymphatic endothelial cells (HLECs). Next, Interleukin 10 knock‐out (Il‐10−/−) mice were used to assess the biological functions of CrF‐EVs in spontaneous mesenteritis and colitis. Moreover, tissue and serum from various cohorts of CD patients were used to determine the prognostic value of miR‐132‐3p. Results: CrF‐EVs significantly attenuated spontaneous mesenteritis and colitis in Il‐10−/− mice via promoting lymphangiogenesis and lymphatic drainage. Using high‐throughput sequencing, we demonstrated that CrF‐EVs significantly increased HLEC proliferation, migration, tube formation and CCL‐21 production in a miR‐132‐3p/RASA1/ERK1/2 axis‐dependent manner. Accordingly, upregulated miR‐132‐3p was observed in patient CrF, positively correlated with lymphangiogenesis while negatively correlated with inflammatory factors (tumour necrosis factor‐α and IL‐6) level. Moreover, serum miR‐132‐3p demonstrated a positive correlation with disease activity. Conclusions: EVs derived from CrF ADSCs, containing elevated levels of miR‐132‐3p, could promote lymphatic function and restrain inflammation of CD. Our results provide a novel insight into the role of mesenteric lymphatics in CD progression and reveal a new potential therapeutic. Key points: Extracellular vesicles (EVs) of creeping fat (CrF) derived adipose stem cells effectively attenuate chronic mesenteritis and colitis in Crohn's disease (CD).The lymphatic vessels play an important role in disease development of CD and their functions are improved by CrF‐EV‐miR‐132‐3p through RASA1/ERK1/2 signaling.MiR‐132‐3p expression is upregulated in CrF and serum of CD patients, and tightly linked with inflammation and disease activity. [ABSTRACT FROM AUTHOR]

The lymphatic network of capillaries and collecting vessels ensures tissue fluid homeostasis, absorption of dietary fats and trafficking of immune cells. Pannexin1 (Panx1) channels allow for the passage of ions and small metabolites between the cytosol and extracellular environment. Panx1 channels regulate the pathophysiological function of several tissues in a sex‐dependent manner. Here, we studied the role of Panx1 in lymphatic function, and potential sex‐dependent differences therein, in Prox1‐CreERT2Panx1fl/fl and Panx1fl/fl control mice. Panx1 expression was higher in lymphatic endothelial cells (LECs) of male mice. Lymphatic vessel morphology was not affected in Prox1‐CreERT2Panx1fl/fl male and female mice. Lymphatic drainage was decreased by 25% in male Prox1‐CreERT2Panx1fl/fl mice, but was similar in females of both genotypes. Accordingly, only male Prox1‐CreERT2Panx1fl/fl mice exhibited tail swelling, pointing to interstitial fluid accumulation in males upon Panx1 deletion in LECs. Moreover, serum triglyceride and free fatty acid levels raised less in Prox1‐CreERT2Panx1fl/fl mice of both sexes in an oral lipid tolerance test. Finally, the percentage of migratory dendritic cells arriving in draining lymph nodes was increased in Prox1‐CreERT2Panx1fl/fl female mice, but was comparable between male mice of both genotypes. Our results point to a LEC‐specific role for Panx1 in the functions of the lymphatic system. [ABSTRACT FROM AUTHOR]

Background: Lymphoedema is a chronic and progressive disease characterised by excessive accumulation of lymph in the interstitial compartment, leading to tissue swelling and fibroadipose deposition. Lymphangiogenesis is partly regulated by ketone body oxidation, and a ketogenic diet (KD) has shown therapeutic efficacy in a preclinical mouse tail lymphoedema model. Therefore, we aimed to investigate the potential therapeutic effect of a KD in patients with secondary lymphoedema. Methods: Nine patients with unilateral stage 2 lymphoedema secondary to lymphadenectomy were included in this quasi‐experimental exploratory study consisting of a short run‐in phase to gradually induce ketosis, followed by a classic KD (CKD) and modified Atkins diet (MAD) phase during which patients consumed a CKD and MAD, respectively. Lymphatic function and oedema volume, the primary outcomes, were assessed at baseline and at the end of both the CKD and MAD phase. Secondary outcomes included health‐related and lymphedema‐specific quality of life (QoL). Results: Seven out of nine patients completed the study protocol. Lymphatic function was improved upon consumption of both a CKD (dermal backflow score [mean ± SD]: 7.29 ± 2.98 vs. 10.86 ± 2.19 at baseline; p = 0.03) and MAD (6.71 ± 2.06; p = 0.02), whereas oedema volume did not decrease during the course of the study (excess limb volume [mean ± SD]: 20.13 ± 10.25% at end of CKD and 24.07 ± 17.77% at end of MAD vs. 20.79 ± 12.96% at baseline; p > 0.99 and p > 0.30, respectively). No changes were observed in health‐related, nor lymphoedema‐specific QoL at the end of CKD and MAD. Conclusions: The consumption of a KD improved lymphatic function and was associated with a clinically meaningful reduction in oedema volume in some patients (3/7 at end of CKD, 2/7 at end of MAD) with unilateral stage 2 secondary lymphoedema. These results highlight the potential of a KD to improve lymphatic function in patients with lymphoedema. However, further studies are required to substantiate our findings. Highlights: Lymphoedema is a chronic and progressive disease characterised by excessive accumulation of lymph in the interstitial compartment due to impaired lymphatic drainage, and ketone body oxidation has been shown to play a critical role in restoring lymphatic drainage and resolving accumulated lymph.In patients with unilateral secondary lymphoedema, consumption of both a classic ketogenic diet (CKD) and a modified Atkins diet (MAD) improved lymphatic function, which was associated with a clinically meaningful reduction in oedema volume in three and two out of seven patients upon consumption of a CKD and a MAD, respectively.The potential of the ketogenic diet as a novel metabolic strategy for the treatment of lymphoedema should be confirmed in a randomised control trial. [ABSTRACT FROM AUTHOR]

Lymphatics participate in reverse cholesterol transport, and their presence in the arterial wall of the great vessels and prior experimental results suggest their possible role in the development of atherosclerosis. The aim of this study was to characterize the lymphatic vasculature of the arterial wall in atherosclerosis. Tissue sections and tissue-cleared aortas of wild-type mice unveiled significant differences in the density of the arterial lymphatic network throughout the arterial tree. Male and female Ldlr−/− and ApoE−/− mice on a Western diet showed sex-dependent differences in plaque formation and calcification. Female mice on a Western diet developed more calcification of atherosclerotic plaques than males. The lymphatic vessels within the aortic wall of these mice showed no major changes regarding the number of lymphatic junctions and end points or the lymphatic area. However, female mice on a Western diet showed moderate dilation of lymphatic vessels in the abdominal aorta and exhibited indications of increased peripheral lymphatic function, findings that require further studies to understand the role of lymphatics in the arterial wall during the development of atherosclerosis. [ABSTRACT FROM AUTHOR]

Physiological properties and function of the lymphatic system is still somewhat of a mystery. We report the current knowledge about human lymphatic vessel contractility and capability of adaptation. A literature search in PubMed identified studies published January 2000–September 2022. Inclusion criteria were studies investigating parameters related to contraction frequency, fluid velocity, and lymphatic pressure in vivo and ex vivo in human lymphatic vessels. The search returned 2885 papers of which 28 met the inclusion criteria. In vivo vessels revealed baseline contraction frequencies between 0.2 ± 0.2 and 1.8 ± 0.1 min1, velocities between 0.008 ± 0.002 and 2.3 ± 0.3 cm/s, and pressures between 4.5 (range 0.5–9.2) and 60.3 ± 2.8 mm Hg. Gravitational forces, hyperthermia, and treatment with nifedipine caused increases in contraction frequency. Ex vivo lymphatic vessels displayed contraction frequencies between 1.2 ± 0.1 and 5.5 ± 1.2 min−1. Exposure to agents affecting cation and anion channels, adrenoceptors, HCN channels, and changes in diameter‐tension properties all resulted in changes in functional parameters as known from the blood vascular system. We find that the lymphatic system is dynamic and adaptable. Different investigative methods yields alternating results. Systematic approaches, consensus on investigative methods, and larger studies are needed to fully understand lymphatic transport and apply this in a clinical context. [ABSTRACT FROM AUTHOR]

Background: Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Despite the various physical therapy and surgical options available, most treatments are palliative and fail to address the underlying lymphatic vascular insufficiency driving lymphedema progression. Stem cell therapy provides a promising alternative in the treatment of various chronic diseases with a wide range of therapeutic effects that reduce inflammation, fibrosis, and oxidative stress, while promoting lymphatic vessel (LV) regeneration. Specifically, stem cell transplantation is suggested to promote LV restoration, rebuild lymphatic circulation, and thus potentially be utilized towards an effective lymphedema treatment. In addition to stem cells, studies have proposed the administration of vascular endothelial growth factor C (VEGFC) to promote lymphangiogenesis and decrease swelling in lymphedema. Aims: Here, we seek to combine the benefits of stem cell therapy, which provides a cellular therapeutic approach that can respond to the tissue environment, and VEGFC administration to restore lymphatic drainage. Materials & Methods: Specifically, we engineered mesenchymal stem cells (MSCs) to overexpress VEGFC using a lentiviral vector (hVEGFC MSC) and investigated their therapeutic efficacy in improving LV function and tissue swelling using near infrared (NIR) imaging, and lymphatic regeneration in a single LV ligation mouse tail lymphedema model. Results: First, we showed that overexpression of VEGFC using lentiviral transduction led to an increase in VEGFC protein synthesis in vitro. Then, we demonstrated hVEGFC MSC administration post‐injury significantly increased the lymphatic contraction frequency 14‐, 21‐, and 28‐days post‐surgery compared to the control animals (MSC administration) in vivo, while also reducing tail swelling 28‐days post‐surgery compared to controls. Conclusion: Our results suggest a therapeutic potential of hVEGFC MSC in alleviating the lymphatic dysfunction observed during lymphedema progression after secondary injury and could provide a promising approach to enhancing autologous cell therapy for treating lymphedema. [ABSTRACT FROM AUTHOR]

Advancements in lymphography technology are essential for comprehensive investigation of the lymphatic system and its function. Here, a shortwave infrared (SWIR) luminescence imaging oflymphatic vessels is proposed in both normal and lymphatic dysfunction in rat models with PbS quantum dots (PbS Qdots). The lymphography with PbS Qdots can clearly and rapidly demonstrate the normal lymphatic morphology in both the tail and hind limb. More importantly, compared to ICG, SWIR luminescence imaging with PbS Qdots can easily identify the dominant lymphatic vessel and node with higher luminescence signal in rats. Moreover, lymphatic pump is identified as segment contracting sections with a size of «1 cm in rat by in vivo SWIR lymphograhy, which propose a direct feature for precise evaluation of lymphatic function. Notably, in vivo SWIR luminescence imaging with PbS Qdots also clearly deciphers the in vivo pattern of morphological and function recovery from lymphatic system in rat model. In summary, SWIR luminescence imaging with PbS Qdots can improve the lymphography and thus deepen the understanding ofthe morphology and structure of the lymphatic system as well as lymphatic function such as lymphatic pump, which will facilitate the diagnosis of lymphatic dysfunction in the future. [ABSTRACT FROM AUTHOR]

Inflammation causes bronchopulmonary dysplasia (BPD), a common lung disease of preterm infants. One reason this disease lacks specific therapies is the paucity of information on the mechanisms regulating inflammation in developing lungs. We address this gap by characterizing the lymphatic phenotype in an experimental BPD model because lymphatics are major regulators of immune homeostasis. We hypothesized that hyperoxia (HO), a major risk factor for experimental and human BPD, disrupts lymphatic endothelial homeostasis using neonatal mice and human dermal lymphatic endothelial cells (HDLECs). Exposure to 70% O2 for 24–72 h decreased the expression of prospero homeobox 1 (Prox1) and vascular endothelial growth factor c (Vegf-c) and increased the expression of heme oxygenase 1 and NAD(P)H dehydrogenase [quinone]1 in HDLECs, and reduced their tubule formation ability. Next, we determined Prox1 and Vegf-c mRNA levels on postnatal days (P) 7 and 14 in neonatal murine lungs. The mRNA levels of these genes increased from P7 to P14, and 70% O2 exposure for 14 d (HO) attenuated this physiological increase in pro-lymphatic factors. Further, HO exposure decreased VEGFR3+ and podoplanin+ lymphatic vessel density and lymphatic function in neonatal murine lungs. Collectively, our results validate the hypothesis that HO disrupts lymphatic endothelial homeostasis. [ABSTRACT FROM AUTHOR]

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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

Lymphatic dysfunction is a pivotal pathological mechanism underlying the development of early atherosclerotic plaques. Potential targets of lymphatic function must be identified to realize the early prevention and treatment of atherosclerosis (AS). The immunity-related GTPase Irgm1 is involved in orchestrating cellular autophagy and apoptosis. However, the effect of Irgm1 on early AS progression, particularly through alterations in lymphatic function, remains unclear. In this study, we confirmed the protective effect of lymphangiogenesis on early-AS in vivo. Subsequently, an in vivo model of early AS mice with Irgm1 knockdown shows that Irgm1 reduces early atherosclerotic plaque burden by promoting lymphangiogenesis. Given that lymphatic endothelial cell (LEC) autophagy significantly contributes to lymphangiogenesis, Irgm1 may enhance lymphatic circulation by promoting LEC autophagy. Moreover, Irgm1 orchestrates autophagy in LECs by inhibiting mTOR and facilitating nuclear translocation of Tfeb. Collectively, these processes lead to lymphangiogenesis. Thus, this study establishes a link between Irgm1 and early AS, thus revealing a novel mechanism by which Irgm1 exerts an early protective influence on AS within the context of lymphatic circulation. The insights gained from this study have the potential to revolutionize the approach and management of AS onset. • Irgm1 promotes lymphangiogenesis by Tfeb translocation and orchestrating moderate LEC autophagy. • Irgm1 is a promising candidate and a potential target for early intervention in AS. • The insights may revolutionize the early prevention and control strategies for AS by enhancing lymphatic function. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the effect of manual lymphatic drainage (MLD) on the insulin resistance parameter (HOMA-IR), glycated hemoglobin (HbA1c), C-peptide, insulin, fasting plasma glucose (FPG), 2h-post-loadglucose (2h-PG) and the concentration of high-sensitivity C-reactive protein (hsCRP) in patients with abnormal body mass index. The study involved 30 patients, including patients with normal body weight (as a control group; group I; n = 14), overweight patients (group II; n = 9) and obese patients (group III; n = 7). Each patient underwent 10 sessions of MLD therapy, 3 times a week for 30 min. In addition, we measured body mass index (BMI) and waist-to-hip ratio (WHR) and performed body composition analysis as well as biochemical tests before MLD therapy (stage 0′) and after MLD therapy (stage 1′). A statistically significant correlation was demonstrated between the concentration of C-peptide, BMI, the amount of visceral adipose tissue (r = 0.87, p = 0.003; r = 0.76, p = 0.003, respectively), and the HOMA-IR index, BMI and the amount of visceral adipose tissue (r = 0.86, p = 0.005; r = 0.84, p = 0.042, respectively), before and after MLD therapy. In overweight patients (group II), a statistically significant (p = 0.041) decrease in the hsCRP level by 2.9 mg/L and a significant (p = 0.050) decrease in the 2h-PG level by 12 mg/dL after the MLD therapy was detected. Moreover, in the group of obese patients (group III), a statistically significant (p = 0.013) decrease in HbA1c level by 0.2% after MLD therapy was demonstrated. Our results indicate that MLD may have a positive effect on selected biochemical parameters, with the most favorable changes in overweight patients. Further studies in a larger number of patients are warranted to confirm our findings, to test in-depth their mechanism, and to investigate clinical benefits of this alternative therapy in patients with abnormal body mass index. [ABSTRACT FROM AUTHOR]

Obesity and metabolic syndrome pose a significant risk for developing cardiovascular disease and remain a critical healthcare challenge. Given the lymphatic system's role as a nexus for lipid absorption, immune cell trafficking, interstitial fluid and macromolecule homeostasis maintenance, the impact of obesity and metabolic disease on lymphatic function is a burgeoning field in lymphatic research. Work over the past decade has progressed from the association of an obese phenotype with Prox1 haploinsufficiency and the identification of obesity as a risk factor for lymphedema to consistent findings of lymphatic collecting vessel dysfunction across multiple metabolic disease models and organisms and characterization of obesity-induced lymphedema in the morbidly obese. Critically, recent findings have suggested that restoration of lymphatic function can also ameliorate obesity and insulin resistance, positing lymphatic targeted therapies as relevant pharmacological interventions. There remain, however, significant gaps in our understanding of lymphatic collecting vessel function, particularly the mechanisms that regulate the spontaneous contractile activity required for active lymph propulsion and lymph return in humans. In this article, we will review the current findings on lymphatic architecture and collecting vessel function, including recent advances in the ionic basis of lymphatic muscle contractile activity. We will then discuss lymphatic dysfunction observed with metabolic disruption and potential pathways to target with pharmacological approaches to improve lymphatic collecting vessel function. [ABSTRACT FROM AUTHOR]

The lymphatic circulation is an important component of the circulatory system in humans, playing a critical role in the transport of lymph fluid containing proteins, white blood cells, and lipids from the interstitial space to the central venous circulation. The efficient transport of lymph fluid critically relies on the rhythmic contractions of collecting lymph vessels, which function to "pump" fluid in the distal to proximal direction through the lymphatic circulation with backflow prevented by the presence of valves. When rhythmic contractions are disrupted or valves are incompetent, the loss of lymph flow results in fluid accumulation in the interstitial space and the development of lymphedema. There is growing recognition that many pharmacological agents modify the activity of ion channels and other protein structures in lymph muscle cells to disrupt the cyclic contraction and relaxation of lymph vessels, thereby compromising lymph flow and predisposing to the development of lymphedema. The effects of different medications on lymph flow can be understood by appreciating the intricate intracellular calcium signaling that underlies the contraction and relaxation cycle of collecting lymph vessels. For example, voltage-sensitive calcium influx through long-lasting ("L-type") calcium channels mediates the rise in cytosolic calcium concentration that triggers lymph vessel contraction. Accordingly, calcium channel antagonists that are mainstay cardiovascular medications, attenuate the cyclic influx of calcium through L-type calcium channels in lymph muscle cells, thereby disrupting rhythmic contractions and compromising lymph flow. Many other classes of medications also may contribute to the formation of lymphedema by impairing lymph flow as an off-target effect. The purpose of this review is to evaluate the evidence regarding potential mechanisms of drug-related lymphedema with an emphasis on common medications administered to treat cardiovascular diseases, metabolic disorders, and cancer. Additionally, although current pharmacological approaches used to alleviate lymphedema are largely ineffective, efforts are mounting to arrive at a deeper understanding of mechanisms that regulate lymph flow as a strategy to identify novel anti-lymphedema medications. Accordingly, this review also will provide information on studies that have explored possible anti-lymphedema therapeutics. [ABSTRACT FROM AUTHOR]

Obesity and metabolic syndrome pose a significant risk for developing cardiovascular disease and remain a critical healthcare challenge. Given the lymphatic system’s role as a nexus for lipid absorption, immune cell trafficking, interstitial fluid and macromolecule homeostasis maintenance, the impact of obesity and metabolic disease on lymphatic function is a burgeoning field in lymphatic research. Work over the past decade has progressed from the association of an obese phenotype with Prox1 haploinsufficiency and the identification of obesity as a risk factor for lymphedema to consistent findings of lymphatic collecting vessel dysfunction across multiple metabolic disease models and organisms and characterization of obesity-induced lymphedema in the morbidly obese. Critically, recent findings have suggested that restoration of lymphatic function can also ameliorate obesity and insulin resistance, positing lymphatic targeted therapies as relevant pharmacological interventions. There remain, however, significant gaps in our understanding of lymphatic collecting vessel function, particularly the mechanisms that regulate the spontaneous contractile activity required for active lymph propulsion and lymph return in humans. In this article, we will review the current findings on lymphatic architecture and collecting vessel function, including recent advances in the ionic basis of lymphatic muscle contractile activity. We will then discuss lymphatic dysfunction observed with metabolic disruption and potential pathways to target with pharmacological approaches to improve lymphatic collecting vessel function.

The lymphatic circulation is an important component of the circulatory system in humans, playing a critical role in the transport of lymph fluid containing proteins, white blood cells, and lipids from the interstitial space to the central venous circulation. The efficient transport of lymph fluid critically relies on the rhythmic contractions of collecting lymph vessels, which function to “pump” fluid in the distal to proximal direction through the lymphatic circulation with backflow prevented by the presence of valves. When rhythmic contractions are disrupted or valves are incompetent, the loss of lymph flow results in fluid accumulation in the interstitial space and the development of lymphedema. There is growing recognition that many pharmacological agents modify the activity of ion channels and other protein structures in lymph muscle cells to disrupt the cyclic contraction and relaxation of lymph vessels, thereby compromising lymph flow and predisposing to the development of lymphedema. The effects of different medications on lymph flow can be understood by appreciating the intricate intracellular calcium signaling that underlies the contraction and relaxation cycle of collecting lymph vessels. For example, voltage-sensitive calcium influx through long-lasting (“L-type”) calcium channels mediates the rise in cytosolic calcium concentration that triggers lymph vessel contraction. Accordingly, calcium channel antagonists that are mainstay cardiovascular medications, attenuate the cyclic influx of calcium through L-type calcium channels in lymph muscle cells, thereby disrupting rhythmic contractions and compromising lymph flow. Many other classes of medications also may contribute to the formation of lymphedema by impairing lymph flow as an off-target effect. The purpose of this review is to evaluate the evidence regarding potential mechanisms of drug-related lymphedema with an emphasis on common medications administered to treat cardiovascular diseases, metabolic disorders, and cancer. Additionally, although current pharmacological approaches used to alleviate lymphedema are largely ineffective, efforts are mounting to arrive at a deeper understanding of mechanisms that regulate lymph flow as a strategy to identify novel anti-lymphedema medications. Accordingly, this review also will provide information on studies that have explored possible anti-lymphedema therapeutics.

Inflammation causes bronchopulmonary dysplasia (BPD), a common lung disease of preterm infants. One reason this disease lacks specific therapies is the paucity of information on the mechanisms regulating inflammation in developing lungs. We address this gap by characterizing the lymphatic phenotype in an experimental BPD model because lymphatics are major regulators of immune homeostasis. We hypothesized that hyperoxia (HO), a major risk factor for experimental and human BPD, disrupts lymphatic endothelial homeostasis using neonatal mice and human dermal lymphatic endothelial cells (HDLECs). Exposure to 70% O2 for 24–72 h decreased the expression of prospero homeobox 1 (Prox1) and vascular endothelial growth factor c (Vegf-c) and increased the expression of heme oxygenase 1 and NAD(P)H dehydrogenase [quinone]1 in HDLECs, and reduced their tubule formation ability. Next, we determined Prox1 and Vegf-c mRNA levels on postnatal days (P) 7 and 14 in neonatal murine lungs. The mRNA levels of these genes increased from P7 to P14, and 70% O2 exposure for 14 d (HO) attenuated this physiological increase in pro-lymphatic factors. Further, HO exposure decreased VEGFR3+ and podoplanin+ lymphatic vessel density and lymphatic function in neonatal murine lungs. Collectively, our results validate the hypothesis that HO disrupts lymphatic endothelial homeostasis.

Objective: Obesity results in lymphatic dysfunction, but the cellular mechanisms that mediate this effect remain largely unknown. Previous studies in obese mice have shown that inducible nitric oxide synthase-expressing (iNOS+) inflammatory cells accumulate around lymphatic vessels. In the current study, we therefore tested the hypothesis that increased expression of iNOS results in nitrosative stress and injury to the lymphatic endothelial cells (LECs). In addition, we tested the hypothesis that lymphatic injury, independent of obesity, can modulate glucose and lipid metabolism. Methods: We compared the metabolic changes and lymphatic function of wild-type and iNOS knockout mice fed a normal chow or high-fat diet for 16 weeks. To corroborate our in vivo findings, we analyzed the effects of reactive nitrogen species on isolated LECs. Finally, using a genetically engineered mouse model that allows partial ablation of the lymphatic system, we studied the effects of acute lymphatic injury on glucose and lipid metabolism in lean mice. Results: The mesenteric lymphatic vessels of obese wild-type animals were dilated, leaky, and surrounded by iNOS+ inflammatory cells with resulting increased accumulation of reactive nitrogen species when compared with lean wild-type or obese iNOS knockout animals. These changes in obese wild-type mice were associated with systemic glucose and lipid abnormalities, as well as decreased mesenteric LEC expression of lymphatic-specific genes, including vascular endothelial growth factor receptor 3 (VEGFR-3) and antioxidant genes as compared with lean wild-type or obese iNOS knockout animals. In vitro experiments demonstrated that isolated LECs were more sensitive to reactive nitrogen species than blood endothelial cells, and that this sensitivity was ameliorated by antioxidant therapies. Finally, using mice in which the lymphatics were specifically ablated using diphtheria toxin, we found that the interaction between metabolic abnormalities caused by obesity and lymphatic dysfunction is bidirectional. Targeted partial ablation of mesenteric lymphatic channels of lean mice resulted in increased accumulation of iNOS+ inflammatory cells and increased reactive nitrogen species. Lymphatic ablation also caused marked abnormalities in insulin sensitivity, serum glucose and insulin concentrations, expression of insulin-sensitive genes, lipid metabolism, and significantly increased systemic and mesenteric white adipose tissue (M-WAT) inflammatory responses. Conclusions: Our studies suggest that increased iNOS production in obese animals plays a key role in regulating lymphatic injury by increasing nitrosative stress. In addition, our studies suggest that obesity-induced lymphatic injury may amplify metabolic abnormalities by increasing systemic and local inflammatory responses and regulating insulin sensitivity. These findings suggest that manipulation of the lymphatic system may represent a novel means of treating metabolic abnormalities associated with obesity.

Despite significant efforts made to treat cardiovascular disease (CVD), more than half of cardiovascular events still occur in asymptomatic subjects devoid of traditional risk factors. These observations underscore the need for the identification of new biomarkers for the prevention of atherosclerosis, the main underlying cause of CVD. Extracellular vesicles (EVs) and lymphatic vessel function are emerging targets in this context. EVs are small vesicles released by cells upon activation or death that are present in several biological tissues and fluids, including blood and lymph. They interact with surrounding cells to transfer their cargo, and the complexity of their biological content makes these EVs potential key players in several chronic inflammatory settings. Many studies focused on the interaction of EVs with the most well-known players of atherosclerosis such as the vascular endothelium, smooth muscle cells and monocytes. However, the fate of EVs within the lymphatic network, a crucial route in the mobilization of cholesterol out the artery wall, is not known. In this review, we aim to bring forward evidence that EVs could be at the interplay between lymphatic function and atherosclerosis by summarizing the recent findings on the characterization of EVs in this setting.

The lymphatic system has many functions, including macromolecules transport, fat absorption, regulation and modulation of adaptive immune responses, clearance of inflammatory cytokines, and cholesterol metabolism. Thus, it is evident that lymphatic function can play a key role in the regulation of a wide array of biologic phenomenon, and that physiologic changes that alter lymphatic function may have profound pathologic effects. Recent studies have shown that obesity can markedly impair lymphatic function. Obesity-induced pathologic changes in the lymphatic system result, at least in part, from the accumulation of inflammatory cells around lymphatic vessel leading to impaired lymphatic collecting vessel pumping capacity, leaky initial and collecting lymphatics, alterations in lymphatic endothelial cell (LEC) gene expression, and degradation of junctional proteins. These changes are important since impaired lymphatic function in obesity may contribute to the pathology of obesity in other organ systems in a feed-forward manner by increasing low-grade tissue inflammation and the accumulation of inflammatory cytokines. More importantly, recent studies have suggested that interventions that inhibit inflammatory responses, either pharmacologically or by lifestyle modifications such as aerobic exercise and weight loss, improve lymphatic function and metabolic parameters in obese mice. The purpose of this review is to summarize the pathologic effects of obesity on the lymphatic system, the cellular mechanisms that regulate these responses, the effects of impaired lymphatic function on metabolic syndrome in obesity, and the interventions that may improve lymphatic function in obesity.

Background: Knowledge of functional parameters that can be used for evaluation of upper extremity lymphatic function is limited. This study aims to evaluate near-infrared fluorescence (NIRF) imaging for evaluation of lymphatic function in the human arm. Methods and Results: Ten healthy male volunteers (age 25.7 ± 1.3 years) were included and examined at two occasions. The lymphatic functional frequency and velocity were examined at baseline, during hyperthermia and after exercise. In addition, the maximum pressure generated by contraction of the lymphatic vessels was estimated. The mean contraction frequency was found to be 0.9 ± 0.4/min, and the mean velocity of the propulsions was 1.1 ± 0.3 cm/s. The average maximal pressure generated by the contraction of the lymphatic vessels was 59 ± 12 mmHg. No significant difference in frequency, velocity, or pumping pressure was found between the two visits (p > 0.05). Local hyperthermia increased contraction frequency significantly, whereas exercise decreased frequency and increased propulsion velocity. Conclusions: The functional lymphatic parameters evaluated by NIRF imaging showed good repeatability with no significant difference between visits. Future examinations should be conducted with standardization of temperature and exercise, as these parameters were shown to alter lymphatic function. [ABSTRACT FROM AUTHOR]

Despite significant efforts made to treat cardiovascular disease (CVD), more than half of cardiovascular events still occur in asymptomatic subjects devoid of traditional risk factors. These observations underscore the need for the identification of new biomarkers for the prevention of atherosclerosis, the main underlying cause of CVD. Extracellular vesicles (EVs) and lymphatic vessel function are emerging targets in this context. EVs are small vesicles released by cells upon activation or death that are present in several biological tissues and fluids, including blood and lymph. They interact with surrounding cells to transfer their cargo, and the complexity of their biological content makes these EVs potential key players in several chronic inflammatory settings. Many studies focused on the interaction of EVs with the most well-known players of atherosclerosis such as the vascular endothelium, smooth muscle cells and monocytes. However, the fate of EVs within the lymphatic network, a crucial route in the mobilization of cholesterol out the artery wall, is not known. In this review, we aim to bring forward evidence that EVs could be at the interplay between lymphatic function and atherosclerosis by summarizing the recent findings on the characterization of EVs in this setting. [ABSTRACT FROM AUTHOR]

The lymphatic system has many functions, including macromolecules transport, fat absorption, regulation and modulation of adaptive immune responses, clearance of inflammatory cytokines, and cholesterol metabolism. Thus, it is evident that lymphatic function can play a key role in the regulation of a wide array of biologic phenomenon, and that physiologic changes that alter lymphatic function may have profound pathologic effects. Recent studies have shown that obesity can markedly impair lymphatic function. Obesity-induced pathologic changes in the lymphatic system result, at least in part, from the accumulation of inflammatory cells around lymphatic vessel leading to impaired lymphatic collecting vessel pumping capacity, leaky initial and collecting lymphatics, alterations in lymphatic endothelial cell (LEC) gene expression, and degradation of junctional proteins. These changes are important since impaired lymphatic function in obesity may contribute to the pathology of obesity in other organ systems in a feed-forward manner by increasing low-grade tissue inflammation and the accumulation of inflammatory cytokines. More importantly, recent studies have suggested that interventions that inhibit inflammatory responses, either pharmacologically or by lifestyle modifications such as aerobic exercise and weight loss, improve lymphatic function and metabolic parameters in obese mice. The purpose of this review is to summarize the pathologic effects of obesity on the lymphatic system, the cellular mechanisms that regulate these responses, the effects of impaired lymphatic function on metabolic syndrome in obesity, and the interventions that may improve lymphatic function in obesity. [ABSTRACT FROM AUTHOR]

The lymphatic system plays a crucial role in maintaining tissue homeostasis, immune response, and fluid balance within the human body. Lymphatic vessels, a key component of this system, undergo complex development and function throughout life. This article provides an overview of the development and function of lymphatic vessels, highlighting their significance in various physiological processes.. [ABSTRACT FROM AUTHOR]

Recently, the presence of lymphatics has been demonstrated and characterized in the dura mater, which is in contrast to the well-accepted view indicating the lack of a classical lymphatic drainage system of the central nervous system (CNS). Moreover, the role of meningeal lymphatics in the pathogenesis of Alzheimer's disease and multiple sclerosis was suggested. However, the possible regulators of the developmental program and function of meningeal lymphatics remain unclear. Here, we aimed at characterizing the lymph flow dependence of the developmental program and function of the meningeal lymphatics. First, we demonstrated that lymphatics present in the dura mater are involved in the uptake and transport of macromolecules from the CNS. Meningeal lymphatics develop during the postnatal period which process involves the maturation of the vessels. The formation of mature meningeal lymphatics coincides with the increase of the drainage of macromolecules from the CNS to the deep cervical lymph nodes. Importantly, the structural remodeling and maturation of meningeal lymphatics is impaired in Plcγ2−/− mice with reduced lymph flow. Furthermore, macromolecule uptake and transport by the meningeal lymphatics are also affected in Plcγ2−/− mice. Collectively, lymph flow-induced mechanical forces are required for the postnatal formation of mature and functional meningeal lymphatic vessels. Defining lymph flow-dependence of the development and function of meningeal lymphatics may lead to better understanding of the pathogenesis of neurological diseases including Alzheimer's disease and multiple sclerosis.

Recently, the presence of lymphatics has been demonstrated and characterized in the dura mater, which is in contrast to the well-accepted view indicating the lack of a classical lymphatic drainage system of the central nervous system (CNS). Moreover, the role of meningeal lymphatics in the pathogenesis of Alzheimer's disease and multiple sclerosis was suggested. However, the possible regulators of the developmental program and function of meningeal lymphatics remain unclear. Here, we aimed at characterizing the lymph flow dependence of the developmental program and function of the meningeal lymphatics. First, we demonstrated that lymphatics present in the dura mater are involved in the uptake and transport of macromolecules from the CNS. Meningeal lymphatics develop during the postnatal period which process involves the maturation of the vessels. The formation of mature meningeal lymphatics coincides with the increase of the drainage of macromolecules from the CNS to the deep cervical lymph nodes. Importantly, the structural remodeling and maturation of meningeal lymphatics is impaired in Plc γ 2 −/− mice with reduced lymph flow. Furthermore, macromolecule uptake and transport by the meningeal lymphatics are also affected in Plc γ 2 −/− mice. Collectively, lymph flow-induced mechanical forces are required for the postnatal formation of mature and functional meningeal lymphatic vessels. Defining lymph flow-dependence of the development and function of meningeal lymphatics may lead to better understanding of the pathogenesis of neurological diseases including Alzheimer's disease and multiple sclerosis. [ABSTRACT FROM AUTHOR]

A local anesthetic, lidocaine, is known to affect cutaneous blood flow when injected into the skin. However, it is unknown if dermal lymphatic function can also be affected. Therefore, we characterized lymphatic function in response to administration of lidocaine with and without epinephrine. Non-invasive near-infrared fluorescence imaging (NIRFI) with intradermal injection of indocyanine green (ICG) was used to characterize the lymphatic 'pumping' function in mice after subcutaneous injection of 2 % lidocaine with and without 1:100,000 epinephrine or saline. NIRFI was performed for 10-20 min immediately after and 1, 3, and 5 h after these interventions. Lymphatic contraction frequencies significantly decreased 10 min after subcutaneous injection of lidocaine and remained plateaued for another 5 min, before returning to baseline. However, addition of 1:100,000 epinephrine to 2 % lidocaine rapidly increased lymphatic contraction frequencies at 5 min post-injection, which returned to baseline levels 15 min later. Injection of saline also increased lymphatic contraction frequency 5 min after injection, which returned to baseline 10 min post-injection. Although lidocaine administration showed a decrease in lymphatic function, the combination of epinephrine with lidocaine resulted in a predominant net effect of increased contractile activity. [ABSTRACT FROM AUTHOR]

The article discusses the causes of axillary web syndrome (AWS) also known as cording which occurs after cancer surgery involving axillary lymph node removal. Other topics discussed include the origin of AWS during post-operative healing, reduced risk of AWS in people with high body mass index (BMI), and strenuous exercise leading to AWS development.