Banxia Xiexin decoction promotes gastric lymphatic pumping by regulating lymphatic smooth muscle cell contraction and energy metabolism in a stress-induced gastric ulceration rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine (TCM) formula Banxia Xiexin decoction (BXD) has definite therapeutic effect in treating stress-induced gastric ulceration (SIGU) and many other gastrointestinal diseases, but its effect on gastric lymphatic pumping (GLP) remains unclear. AIM OF THE STUDY: Elucidating the role of GLP in SIGU and BXD treatment, and exploring the molecular mechanisms of GLP regulation. MATERIALS AND METHODS: In vivo GLP imaging were performed on SIGU rat model, and the lymphatic dynamic parameters were evaluated. Gastric antrum tissues and serum were collected for macroscopic, histopathological and ulcerative parameters analysis. Gastric lymphatic vessel (GLV) tissues were collected for RNA-Seq assays. Differentially expressed genes (DEGs) were screened from RNA-Seq result and submitted for transcriptomic analysis. Key DEGs and their derivative proteins were measured by qRT-PCR and WB. RESULTS: GLP was significantly suppressed in SIGU rats. BXD could recover GLP, ameliorate stomach lymphostasis, and alleviate the ulcerative damage. Transcriptome analysis of GLV showed the top up-DEGs were concentrated in smooth muscle contraction signaling pathway, while the top the down-DEGs were concentrated in energy metabolism pathways especially fatty acid degradation pathway, which indicated BXD can promote lymphatic smooth muscle contraction, regulate energy metabolism, and reduce fatty acid degradation. The most possible target of these mechanisms was the lymphatic smooth muscle cells (LSMCs) which drove the GLP. This speculation was further validated by the qRT-PCR and WB assessments for the level of key genes and proteins. CONCLUSIONS: By activating the smooth muscle contraction signaling pathway, restoring energy supply, modulating energy metabolism program and reducing fatty acid degradation, BXD effectively recovered GLP, mitigated the accumulation of inflammatory cytokines and metabolic wastes in the stomach, which importantly contributes to its efficacy in treating SIGU.

Lymphangiogenesis: A new strategy for heart disease treatment (Review).

Heart disease remains a global health challenge, contributing notably to morbidity and mortality. The lymphatic vasculature, an integral component of the cardiovascular system, plays a crucial role in regulating essential physiological processes, including fluid balance, transportation of extravasated proteins and immune cell trafficking, all of which are important for heart function. Through thorough scientometric analysis and extensive research, the present review identified lymphangiogenesis as a hotspot in cardiovascular disease research, and the mechanisms underlying impaired cardiac lymphangiogenesis and inadequate lymph drainage in various cardiovascular diseases are discussed. Furthermore, the way used to improve lymphangiogenesis to effectively regulate a variety of heart diseases and associated signaling pathways was investigated. Notably, the current review also highlights the impact of Traditional Chinese Medicine (TCM) on lymphangiogenesis, aiming to establish a clinical basis for the potential of TCM to improve cardiovascular diseases by promoting lymphangiogenesis.

A new lymphedema treatment using pyro-drive jet injection.

Lymphedema, resulting from impaired lymphatic drainage, causes inflammation, fibrosis and tissue damage leading to symptoms such as limb swelling and restricted mobility. Despite various treatments under exploration, no standard effective therapy exists. Here a novel technique using the pyro-drive jet injection (PJI) was used to create artificial clefts between collagen fibers, which facilitated the removal of excess interstitial fluid. The PJI was used to deliver a mixture of lactated Ringer's solution and air into the tail of animals with secondary skin edema. Edema levels were assessed using micro-CT scanning. Histopathological changes and neovascularization were evaluated on the injury-induced regenerative tissue. Regarding tissue remodeling, we focused on connective tissue growth factor (CTGF) and vascular endothelial growth factor (VEGF)-C. PJI markedly diminished soft tissue volume in the experimental lymphedema animals compared to the non-injected counterparts. The PJI groups exhibited a significantly reduced proportion of inflammatory granulation tissue and an enhanced density of lymphatic vessels and α-smooth muscle actin (αSMA)-positive small vessels in the fibrous granulation tissue compared to the controls. In addition, PJI curtailed the prevalence of CTGF- and VEGF-C-positive cells in regenerative tissue. In a lymphedema animal model, PJI notably ameliorated interstitial edema, promoted lymphatic vessel growth, and bolstered αSMA-positive capillaries in fibrous granulation tissue. PJI's minimal tissue impact post-lymph node dissection indicates significant potential as an early, standard preventative measure. Easily applied in general clinics without requiring specialized training, it offers a cost-effective and highly versatile solution to the management of lymphedema.

Application of complete decongestive therapy after lymphaticovenular anastomosis of the lower limb combined with liposuction-A retrospective study research.

BACKGROUND: Complete decongestive therapy (CDT) is a conservative treatment for lymphedema that combines interventions and lifestyle changes. We evaluated the application of CDT after lymphaticovenular anastomosis (LVA) of the lower limb combined with liposuction. METHODS: A total of 55 patients who underwent LVA of the lower limb combined with liposuction from January 2021 to July 2022 were enrolled in the study. The patients were divided into groups A (n = 24) and B (n = 31) according to whether they adhered to CDT treatment during the 12-month follow-up. Group A was the non-adherence CDT group and Group B was the adherence CDT group. Lower Extremity Lymphedema Index (LELI) and Lymphoedema Functioning, Disability, and Health Questionnaire for Lower Limb Lymphoedema (Lymph-ICF-LL) were used as prognostic indicators to observe the remission of postoperative lymphedema symptoms in the two groups. RESULTS: At 6-month and 12-month follow-up, LELI and the score of Lymph-ICF-LL in group B and group A were lower than before the operation (p < .05). The circumference of the affected limb was reduced, and the quality of life was improved in both groups after the operation. The reduction of LELI and Lymph-ICF-LL in group B was higher than in group A, and the difference was statistically significant (p < .05). CONCLUSION: This study preliminarily proves the effectiveness of CDT after LVA of the lower limb combined with liposuction, which can maintain and strengthen the surgical effect. Further, CDT treatment is still needed after the operation, which is necessary to reduce the circumference of the affected limb and improve patients' quality of life.

Treatment of Rat Lymphedema by Propeller Lymphatic Tissue Flap Combined with Nanofibrillar Collagen Scaffolds.

BACKGROUND: The aim of our study was to evaluate a new propeller vascularized lymphatic tissue flap (pVLNT) combined with aligned nanofibrillar collagen scaffolds (CS) (BioBridge) in reducing lymphedema in the rat lymphedema model. METHODS: Unilateral left hindlimb lymphedema was created in 15 female Sprague-Dawley rats following inguinal and popliteal lymph nodes (LN) resection and radiation. An inguinal pVLNT was elevated from the contralateral groin and transferred through a skin tunnel to the affected groin. Four collagen threads were attached to the flap and inserted in the hindlimb at the subcutaneous level in a fan shape. The three study groups consisted of group A (control), group B (pVLNT), and group C (pVLNT + CS). Volumetric analysis of both hindlimbs was performed using micro-computed tomography imaging before the surgery (at initial time point) and then at 1 and 4 months, postoperatively, and the relative volume difference (excess volume) was measured for each animal. Lymphatic drainage was assessed by indocyanine green (ICG) fluoroscopy for number and morphology of new collectors and the time required for ICG to move from injection point to the midline. RESULTS: Four months after the induction of lymphedema, an increased relative volume difference remained in group A (5.32 ± 4.74%), while there was a significant relative volume reduction in group B (-13.39 ± 8.55%) and an even greater reduction in group C (-14.56 ± 5.04%). ICG fluoroscopy proved the functional restoration of lymphatic vessels and viability of pVLNT in both B and C groups. Notably, only group C demonstrated statistically significant improvements in lymphatic pattern/morphology and in the number of lymphatic collectors as compared with the control group A. CONCLUSION: The pedicle lymphatic tissue flap combined with SC is an effective procedure for the treatment of lymphedema in rats. It can be easily translated into treatment of humans' lower and upper limb lymphedema and further clinical studies are warranted.

Lymphangiogenesis after nonvascularized lymph node transplantation: Lymphangiographic findings in mice and minipigs.

The establishment of new connections after NVLNT (non-vascularized lymph node transplantation) is still poorly understood. The purpose of this study was to investigate lymphatic connections after NVLNT using lymphangiography. In a mice model, 40 mice were allocated to undergo NVLNT or sham surgery. On day 21 after NVLNT, the lymphatic vessels were observed on near-infrared fluorescence imaging with indocyanine green. In a minipig model, 12 minipigs underwent NVLNT. On day 14 after NVLNT, the transplanted lymph node and donor site were checked by ultrasound, and minipigs with viable transplanted LNs were allocated to lipiodol lymphangiography or MR lymphangiography groups. Transplanted LN engraftment was examined with immunohistochemical staining. After NVLNT in mice, the signal intensities in the popliteal region at 3 minutes and 5 minutes were higher in the transplanted side than the control side (21.3 ± 8.1 vs. 11.0 ± 4.6 at 3 minutes, 26.7 ± 6.8 vs. 19.7 ± 5.9 at 5 minutes), while in the sham group, there were no significant differences between sides. In minipigs, lipiodol lymphangiography (n = 5) showed Lipiodol accumulation in transplanted LNs with innumerable newly formed lymphatic vessels and lymphovenous shunts. MR lymphangiography (n = 5) showed higher enhancement on the transplanted side compared to the control side. Histology showed successful engraftment of transplanted LNs in 16 out of 20 (80%) mice and 9 out of 12 (75%) minipigs. Omnidirectional lymphangiogenesis forming a dense lymphatic network and spontaneous formation of lymphovenous shunts were shown after NVLNT.

Efficacy of Lymphaticovenular Anastomosis for Secondary Upper Extremity Lymphedema: Treatment Strategies with Effects of Compression Therapy Discontinuation and Site-Specific Evaluation of the Upper Extremity.

Background: Lymphaticovenular anastomosis (LVA) has recently become a mainstream surgical treatment for lymphedema and is a useful treatment option in addition to conservative therapies such as compression therapy, exercise therapy, and lymphatic drainage. We performed LVA with the goal of stopping compression therapy and report the effect of LVA on secondary lymphedema of the upper extremities. Methods and Results: The participants were 20 patients with secondary lymphedema of the upper extremities categorized as stage 2 or 3 according to the International Society of Lymphology classification. We measured and compared the upper limb circumference at six locations before and 6 months after LVA. Significant decreases in circumference after surgery were observed at 8 cm proximal to the elbow, the elbow joint, 5 cm distal to the elbow, and the wrist joints, but not at 2 cm distal to the axilla or the dorsum of the hand. At more than 6 months postoperatively, eight patients who had been wearing compression gloves were no longer required to wear them, and three patients who had been wearing both sleeves and gloves were no longer required to wear them. Conclusions: LVA is effective in the treatment of secondary lymphedema of the upper extremities, particularly in improving elbow circumference, and is one of the treatments that contributes significantly to the improvement of quality of life. For severe cases with limited range of motion of the elbow joint, LVA should be performed first. Based on these results, we present an algorithm for upper extremity lymphedema treatment.

Therapeutic Lymphangiogenesis Is a Promising Strategy for Secondary Lymphedema.

Secondary lymphedema is caused by lymphatic insufficiency (lymphatic drainage failure) following lymph node dissection during the surgical treatment or radiation therapy of breast or pelvic cancer. The clinical problems associated with lymphedema are reduced quality of life in terms of appearance and function, as well as the development of skin ulcers, recurrent pain, and infection. Currently, countermeasures against lymphedema are mainly physical therapy such as lymphatic massage, elastic stockings, and skin care, and there is no effective and fundamental treatment with a highly recommended grade. Therefore, there is a need for the development of a fundamental novel treatment for intractable lymphedema. Therapeutic lymphangiogenesis, which has been attracting attention in recent years, is a treatment concept that reconstructs the fragmented lymphatic network to recover lymphatic vessel function and is revolutionary to be a fundamental cure. This review focuses on the translational research of therapeutic lymphangiogenesis for lymphedema and outlines the current status and prospects in the development of therapeutic applications.

Diagnosis and Treatment of Post-Prostatectomy Lymphedema: What's New?

Lymphedema is a chronic progressive disorder that significantly compromises patients' quality of life. In Western countries, it often results from cancer treatment, as in the case of post-radical prostatectomy lymphedema, where it can affect up to 20% of patients, with a significant disease burden. Traditionally, diagnosis, assessment of severity, and management of disease have relied on clinical assessment. In this landscape, physical and conservative treatments, including bandages and lymphatic drainage have shown limited results. Recent advances in imaging technology are revolutionizing the approach to this disorder: magnetic resonance imaging has shown satisfactory results in differential diagnosis, quantitative classification of severity, and most appropriate treatment planning. Further innovations in microsurgical techniques, based on the use of indocyanine green to map lymphatic vessels during surgery, have improved the efficacy of secondary LE treatment and led to the development of new surgical approaches. Physiologic surgical interventions, including lymphovenous anastomosis (LVA) and vascularized lymph node transplant (VLNT), are going to face widespread diffusion. A combined approach to microsurgical treatment provides the best results: LVA is effective in promoting lymphatic drainage, bridging VLNT delayed lymphangiogenic and immunological effects in the lymphatic impairment site. Simultaneous VLNT and LVA are safe and effective for patients with both early and advanced stages of post-prostatectomy LE. A new perspective is now represented by the combination of microsurgical treatments with the positioning of nano fibrillar collagen scaffolds (BioBridgeTM) to favor restoring the lymphatic function, allowing for improved and sustained volume reduction. In this narrative review, we proposed an overview of new strategies for diagnosing and treating post-prostatectomy lymphedema to get the most appropriate and successful patient treatment with an overview of the main artificial intelligence applications in the prevention, diagnosis, and management of lymphedema.

[Research progress of combined surgical treatment of lymphedema based on vascularized lymph node transfer].

Objective: To summarize the research progress of combined surgical treatment of lymphedema based on vascularized lymph node transfer (VLNT), and to provide systematic information for combined surgical treatment of lymphedema. Methods: Literature on VLNT in recent years was extensively reviewed, and the history, treatment mechanism, and clinical application of VLNT were summarized, with emphasis on the research progress of VLNT combined with other surgical methods. Results: VLNT is a physiological operation to restore lymphatic drainage. Multiple lymph node donor sites have been developed clinically, and two hypotheses have been proposed to explain its mechanism for the treatment of lymphedema. But it has some inadequacies such as slow effect and limb volume reduction rate less than 60%. To address these inadequacies, VLNT combined with other surgical methods for lymphedema has become a trend. VLNT can be used in combination with lymphovenous anastomosis (LVA), liposuction, debulking operation, breast reconstruction, and tissue engineered material, which have been shown to reduce the volume of affected limbs, reduce the incidence of cellulitis, and improve patients' quality of life. Conclusion: Current evidence shows that VLNT is safe and feasible in combination with LVA, liposuction, debulking operation, breast reconstruction, and tissue engineered material. However, many issues need to be solved, including the sequence of two surgeries, the interval between two surgeries, and the effectiveness compared with surgery alone. Rigorous standardized clinical studies need to be designed to confirm the efficacy of VLNT alone or in combination, and to further discuss the subsistent issues in the use of combination therapy.

Treatment of Advanced Male Genital Lymphedema With a Complete Functional Lymphatic System Pedicled Transfer.

OBJECTIVE: To evaluate the functional efficacy of the superficial circumflex iliac artery perforator (SCIP) -lymphatic pedicled flap in the treatment of advanced male genital lymphedema. METHODS: From February 2018 to January 2022, we treated 26 male patients with scrotal and penoscrotal advanced lymphedema using reconstructive lymphatic surgery. Isolated scrotal involvement was seen in 15 patients, and 11 patients had penoscrotal involvement. Excision of genital lymphedematous fibrotic tissue was followed by reconstruction utilizing the SCIP-lymphatic flap. Patient characteristics, intraoperative data, and postoperative results were evaluated. RESULTS: The mean patient age was 39 ± 4.6, and the mean follow-up time was 44.9 months. the SCIP-lymphatic flap was used to reconstruct partial (n = 11) or total (n = 15) scrotum and used to reconstruct total penile skin in 9 cases and partial in 2 cases. The flap survival rate was 100%. Cellulitis rates were dramatically reduced after reconstruction (P value <.001). The mean genital lymphedema score (GLS) after surgery was 0.05, which was significantly lower than the preoperative 1, 6.2 (P < .001). The median Glasgow Benefit Inventory (GBI) total score was +41, all 26 patients (100%) showed a degree of quality of life improvement. CONCLUSION: The pedicled SCIP lymphatic transfer approach in advanced male genital lymphedema can provide a durable complete functional lymphatic system that improves the appearance and genital lymphatic drainage. This leads to an improvement in quality of life as well as in sexual functions.

Impact of Goreisan components on rat mesenteric collecting lymphatic vessel pumping.

BACKGROUND: Goreisan is a traditional herbal formulation with diuretic properties tested as a clinical therapeutic to alleviate lymphedema in Japan. The present study aimed to determine how Goreisan and its five different components affect lymphatic pump function. METHODS: Mesenteric collecting lymphatics were isolated from anesthetized Sprague-Dawley rats and mounted on resistance-matched glass micropipettes in a 37°C physiological salt solution bath for studies. Diameter was continuously measured to obtain the following lymphatic pump parameters: contraction frequency (CF), end diastolic diameter (EDD), and end systolic diameter (ESD), contraction amplitude (AMP), ejection fraction (EF), and fractional pump flow (FPF). Goreisan and each of its components (Cinnamomi Cortex, Atractylodis Rhizoma, Alismatis Rhizoma, Polyporus, and Poria) were applied to the bath at concentrations of 1-30 µg/mL. RESULTS: The results show that while Goreisan causes no significant changes to lymphatic pumping, Alismatis Rhizoma and Polyporus each significantly reduce CF and FPF. In addition, rats that received oral administration of Goreisan and Alismatis Rhizoma for 1 week had elevated expression of VEGFR-3 in their mesenteric collecting lymphatics. CONCLUSIONS: Collectively, the results suggest that some components of Goreisan have a direct, rapid impact on lymphatic pumping. These findings provide new insights but also raise new questions about the therapeutic potential of Goreisan in patients with secondary lymphedema.

Intranodal Lymphangiography and Embolization for the Treatment of Early Postoperative Lymphatic Leaks after Pelvic Surgery.

PURPOSE: To assess outcome and predictors of outcome after lymphatic embolization (LE) for early postoperative lymphatic leak after pelvic surgery. MATERIAL AND METHODS: Lymphangiography (LG) procedures performed between May 2015 and February 2020 for postoperative intraperitoneal lymphatic leaks after pelvic surgery were reviewed. Treatment indication was lymphatic drainage of >500 mL/d persisting for >1 week. LE was performed by injecting glue into the iliac lymph node. Fisher exact and Wilcoxon rank-sum tests were used for comparative analysis, and logistic regression was used to assess predictors of outcome. RESULTS: LG was performed in 71 patients. A leak was demonstrated in 69 patients who underwent LE. The mean drainage was 1,329 mL/d ± 773. Catheters were removed in 49 (69.0%) patients after 1 procedure and in 69 (97.2%) patients after a mean of 1.3 procedures. The mean drainage at the time of catheter removal was 157 mL/d ± 100. Failure occurred in 12 (16.9%) cases, including 2 (2.8%) cases of unsuccessful catheter removal and 10 (14.1%) cases of catheter reinsertion owing to recurrent ascites (n = 3) and lymphoceles (n = 7). Older age and drainage of >1,500 mL/d were associated with failure (P = .004). Drainage of >1,500 mL/d was associated with a post-LE catheter dwell time of longer than 1 week (P = .024). Minor adverse events were noted in 4 (5.6%) patients who presented with transient leg swelling. CONCLUSIONS: LE was effective for treating pelvic surgery-related lymphatic leaks. Reintervention may be required. Drainage of >1,500 mL/d was associated with clinical failure and a post-LE catheter dwell time of longer than 1 week.

A Lymphatic Drainage Robot for Lymphedema Rehabilitation.

Lymphedema is a medical condition that results in swelling and discomfort in human arms or legs. Caused due to the build-up of lymph fluid in the tissues under the skin, lymphedema commonly affects one of the arms or legs and it is an incurable condition that requires treatment for control. A common treatment is manual lymphatic drainage (MLD), a massage therapy to remove the excess lymphatic fluid out of the tissues back into the lymphatic vessels. This paper proposes a portable and mobile device, lymphatic drainage robot (LDR), as an alternative to MLD. The prototype LDR, a combination of soft and hard robotic hardware, stimulates the lymphatic system. The robot climbs up the human limb, i.e., an arm or a leg, while applying radial pressure on the skin to remove the excess lymph fluid into the lymph vessels towards the upper side of the limb. The preliminary design of the device stipulated in this paper can be transformed into a product that can be commercially-produced and provided directly to the rehabilitation clinics and lymphedema patients. Clinical relevance - This paper presents a working prototype of an autonomous robotic product that simulates MLD towards the rehabilitation of lymphedema condition.

[Autologous Breast Reconstruction in Conjuction with Lymphatic Microsurgery in Breast Cancer-Related Lymphedema]. / Autologe Brustrekonstruktion und lymphorekonstruktive Chirurgie nach Mastektomie bei Mammakarzinom-assoziiertem LymphödemAutologe Brustrekonstruktion in Kombination mit lymphorekonstruktiver ChirurgieCombined Surgical Treatment of Breast Cancer-Related Lymphedema and Autologous Breast Reconstruction After Mastectomy.

Breast cancer-related lymphedema of the upper extremity is the most significant non-oncological complication of tumour therapy, leading to functional impairment and impacting patients' quality of life. Autologous breast reconstruction per se effectively reduces incidence and stage of lymphedema after breast cancer treatment by surgical angiogenesis. In addition, modern surgical techniques for treating lymphedema are effective in reducing limb volume, circumference and functional impairment, and improving patients' quality of life, body image, integrity and local immunocompetence. Reconstructive surgery, including lymphovenous anastomoses (LVA) and vascularised lymph node transfer (VLNT), have been shown to rearrange or restore lymphatic flow and prevent stage progression. For patients with breast cancer-related lymphedema after mastectomy, autologous breast reconstruction in conjunction with lymphatic microsurgery using VLNT, LVA or a combination of these procedures offers the option of holistic and single-stage restoration in modern senology. Extensive scar release in the axilla is a crucial component of the surgical technique, aiming to prepare the recipient bed for the VLN transplant and to allow for the functional recruitment of remaining lymph vessels of the upper extremity. This article presents the indications, preoperative diagnostic evaluation, surgical techniques and precautions, complications and results of combined lymphatic and breast restoration.

Terapia descongestiva como complemento a la cirugía de anastomosis linfáticovenosas y transferencia de linfonodos vascularizados: Una revisión de la literatura / Decongestive therapy as an adjunct to lymphatic-venous anastomosis surgery and vascularized lymph node transfer: A review of the literature

Resumen Introducción: El linfedema es una enfermedad inflamatoria crónica que afecta cerca de 250 millones de personas en el mundo. El tratamiento tradicional es la terapia descongestiva. Últimamente, existe la opción de complementar el tratamiento tradicional con procedimientos quirúrgicos fisiológicos como anastomosis linfáticovenosas y transferencia de linfonodos vascularizados. Sin embargo, la evidencia del uso de la terapia descongestiva en los cuidados pre y posoperatorios en estas cirugías es limitada. Objetivo: Evaluar el uso de terapia descongestiva como complemento a la cirugía de linfedema mediante anastomosis linfáticovenosas y transferencia de linfonodos vascularizados. Materiales y Método: Se realizó una revisión de la literatura en las siguientes bases de datos: Cochrane, Pubmed y Google académico, utilizando los siguientes términos mesh: "anastomosis, surgical", "lymphedema", "perioperative care", "microsurgery", "rehabilitation", "therapy", "lymph nodes", "bypass", "lymphedema and microsurgery". Se incluyó aquellos artículos que describían el uso de la terapia descongestiva en los cuidados pre- y posoperatorios. Resultados: Se identificó un total de 201 artículos y 12 fueron incluidos en el análisis. La evidencia reporta que las terapias más usadas en el cuidado pre- y posoperatorio son compresión, drenaje linfático manual y tratamientos personalizados. Sin embargo, la mayoría de los autores hace una descripción vaga de las terapias mencionadas. Discusión y Conclusión: La evidencia respecto al uso de terapia descongestiva como tratamiento complementario es débil. Los expertos recomiendan su uso, sin embargo, se necesitan futuras investigaciones que describan el uso de cada uno de sus componentes como complemento de procedimientos quirúrgicos fisiológicos para el manejo del linfedema.

Background: Lymphedema is a disease that affects about 250 million people around the world. The traditional treatment is decongestive therapy. In the past years, there is the option to complementing the traditional treatment with physiological surgical procedures such as lymphatic-venous anastomosis (LVA) and vascularized lymph node transfer (VLNT). However, the evidence for the use of decongestive therapy in pre- and post-operative care in these surgeries is limited. Aim: To evaluate the use of decongestive therapy as a complement to lymphedema surgery such a lymphatic-venous anastomosis and transfer of vascularized lymph nodes. Materials and Method: A literature review was carried out in the following databases: Cochrane, Pubmed and Academic Google, using the following mesh terms: "anastomosis, surgical", "lymphedema", "perioperative care", "microsurgery", "rehabilitation", "therapy", "lymph nodes","bypass", "lymphedema and microsurgery". "Those articles that described the use of decongestive therapy in pre- and post-operative care were included. Results: 201 articles were identified and 12 were included in the analysis. The evidence reports that the most used therapies in pre- and post-operative care are compression, manual lymphatic drainage and personalized treatments. However, most of the authors give a vague description of the mentioned therapies. Discussion and Conclusion: The evidence regarding the use of decongestive therapy as a complementary treatment is weak. Experts recommend its use; however, future research is needed to describe the use of each of its components as a complement to physiological surgical procedures for the management of lymphedema.

Persistent popliteal lymphatic muscle cell coverage defects despite amelioration of arthritis and recovery of popliteal lymphatic vessel function in TNF-Tg mice following anti-TNF therapy.

While rheumatoid arthritis patients and tumor necrosis factor transgenic (TNF-Tg) mice with inflammatory-erosive arthritis display lymphatic drainage deficits, the mechanisms responsible remain unknown. As ultrastructural studies of joint-draining popliteal lymphatic vessels (PLVs) in TNF-Tg mice revealed evidence of lymphatic muscle cell (LMC) damage, we aimed to evaluate PLV-LMC coverage in TNF-Tg mice. We tested the hypothesis that alpha smooth muscle actin (αSMA)+ PLV-LMC coverage decreases with severe inflammatory-erosive arthritis, and is recovered by anti-TNF therapy facilitated by increased PLV-LMC turnover during amelioration of joint disease. TNF-Tg mice with established disease received anti-TNF monoclonal antibody (mAb) or placebo IgG isotype control mAb therapy (n = 5) for 6-weeks, while wild-type (WT) littermates (n = 8) received vehicle (PBS). Bromodeoxyuridine (BrdU) was also administered daily during the treatment period to monitor PLV-LMC turnover. Effective anti-TNF therapy was confirmed by longitudinal assessment of popliteal lymph node (PLN) volume via ultrasound, PLV contraction frequency via near-infrared imaging of indocyanine green, and ankle bone volumes via micro-computed tomography (micro-CT). Terminal knee micro-CT, and ankle and knee histology were also performed. PLVs were immunostained for αSMA and BrdU to evaluate PLV-LMC coverage and turnover, respectively, via whole-mount fluorescent microscopy. Anti-TNF therapy reduced PLN volume, increased talus and patella bone volumes, and reduced tarsal and knee synovial areas compared to placebo treated TNF-Tg mice (p < 0.05), as expected. Anti-TNF therapy also increased PLV contraction frequency at 3-weeks (from 0.81 ± 1.0 to 3.2 ± 2.0 contractions per minute, p < 0.05). However, both anti-TNF and placebo treated TNF-Tg mice exhibited significantly reduced αSMA+ PLV-LMC coverage compared to WT (p < 0.05). There was no correlation of αSMA+ PLV-LMC coverage restoration with amelioration of inflammatory-erosive arthritis. Similarly, there was no difference in PLV-LMC turnover measured by BrdU labeling between WT, TNF-Tg placebo, and TNF-Tg anti-TNF groups with an average of < 1% BrdU+ PLV-LMCs incorporated per week. Taken together these results demonstrate that PLV-LMC turnover in adult mice is limited, and that recovery of PLV function during amelioration of inflammatory-erosive arthritis occurs without restoration of αSMA+ LMC coverage. Future studies are warranted to investigate the direct and indirect effects of chronic TNF exposure, and the role of proximal inflammatory cells on PLV contractility.

Injection Effect of Anti-CD3 Monoclonal Antibody on Primo Vessel in Lymph Vessel of Rabbit with Lipopolysaccharide-Induced Inflammation.

Background: The primo vascular system can be viewed as a circulatory system that plays a therapeutic function in regenerating the body tissue. The anti-CD3 monoclonal antibody was used as an immunotherapeutic agent to treat the novel coronavirus infection (COVID-19). Objectives: In this study, we observed the effect of injecting lymph nodes with Foralumab, an anti- human CD3 epsilon therapeutic monoclonal antibody, on primo vessels. Methods: The structure and atomic stoichiometry of the antibody were determined by transmission electron microscopy and energy dispersive spectroscopy. Alcian blue dying solution was injected into the lymph nodes of the abdominal vena cava of rabbits, and the solution further flowed into the lymph vessels. Results: A primo vessel with primo nodes stained with Alcian blue was clearly visible in the lymph vessel. By injecting Foralumab into lymph nodes of rabbits with lipopolysaccharide-induced inflammation, the floating primo vessel in the lymph vessel appeared thicker and was distinctly visible. Conclusion: The observation of the primo vessel post-treated with Foralumab in the inflamed lymphatic system suggests the possibility of a functional role of the primo vascular circulatory system in pathophysiological conditions.

Lipid droplet degradation by autophagy connects mitochondria metabolism to Prox1-driven expression of lymphatic genes and lymphangiogenesis.

Autophagy has vasculoprotective roles, but whether and how it regulates lymphatic endothelial cells (LEC) homeostasis and lymphangiogenesis is unknown. Here, we show that genetic deficiency of autophagy in LEC impairs responses to VEGF-C and injury-driven corneal lymphangiogenesis. Autophagy loss in LEC compromises the expression of main effectors of LEC identity, like VEGFR3, affects mitochondrial dynamics and causes an accumulation of lipid droplets (LDs) in vitro and in vivo. When lipophagy is impaired, mitochondrial ATP production, fatty acid oxidation, acetyl-CoA/CoA ratio and expression of lymphangiogenic PROX1 target genes are dwindled. Enforcing mitochondria fusion by silencing dynamin-related-protein 1 (DRP1) in autophagy-deficient LEC fails to restore LDs turnover and lymphatic gene expression, whereas supplementing the fatty acid precursor acetate rescues VEGFR3 levels and signaling, and lymphangiogenesis in LEC-Atg5-/- mice. Our findings reveal that lipophagy in LEC by supporting FAO, preserves a mitochondrial-PROX1 gene expression circuit that safeguards LEC responsiveness to lymphangiogenic mediators and lymphangiogenesis.

Three-Dimensional Visualization of Blood and Lymphatic Vessels in the Adult Zebrafish Heart by Chemical Clearing.

Unlike humans, the zebrafish can repair and regenerate its heart following injury. Understanding the molecular and physiological mechanisms of heart regeneration is critical in developing pro-regenerative strategies for clinical application. The cardiac lymphatic and non-lymphatic vasculature both respond to injury in zebrafish and are instrumental in driving optimal repair and regeneration. However, progress has been impeded by an inability to obtain high resolution images to clearly visualize and thus to fully understand the vascular responses in the injured heart and how this might intersect with successful repair and regeneration in humans.In this chapter, we describe a chemical clearing approach using Clear Unobstructed Brain/Body Imaging Cocktails and Computational analysis (CUBIC), for obtaining high resolution images of the adult zebrafish heart. This approach permits three-dimensional reconstruction of cardiac vasculature throughout the entire organ. By applying CUBIC methodology to tissues from transgenic zebrafish reporter lines or in conjunction with immunofluorescent staining, optical slices can be be generated, negating the need for standard tissue processing and sectioning procedures and yielding higher resolution images. The resultant images enable a holistic view of the coronary blood and lymphatic vasculature during heart injury and regeneration. Herein, we describe our protocol for visualizing vessels in the adult zebrafish heart using these approaches.