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Hossain L, Gomes KP, Safarpour S, Gibson SB. The microenvironment of secondary lymphedema. The key to finding effective treatments? Biochim Biophys Acta Mol Basis Dis 2025; 1871:167677. [PMID: 39828048 DOI: 10.1016/j.bbadis.2025.167677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/02/2025] [Accepted: 01/15/2025] [Indexed: 01/22/2025]
Abstract
Lymphedema is characterized by the swelling of extremities due to the accumulation of interstitial fluids. It is a painful and devastating disease that increases the risk of infections and destroys patients' quality of life. Secondary lymphedema is caused by damage to the lymphatic system due to infections, obesity, surgery, and cancer treatments. This damage fails to be repaired and leads to fluid accumulation, tissue remodeling, inflammation, and ultimately fibrosis. The lymphedema microenvironment is altered by stress, immune dysfunction, and changes in metabolism. Stress in the microenvironment includes increased hypoxia and oxidative stress but how this contributes to lymphedema progression is unclear. The immune system plays a critical role in lymphedema through T cell helper type 2 (Th2) immune responses and the infiltration of macrophages into lymphedematous tissue. The inflammatory cytokines released by immune cells lead to tissue remodeling and fibrosis. There are also changes in metabolism in the lymphedema microenvironment with altered lipid oxidation, ketone body oxidation, and glycolysis. How these changes affect lymphedema and treatment interventions has been the focus of clinical trials. Lymphedema is also associated with cancer and obesity through damage to the lymphatic system. This review will illustrate microenvironmental changes in lymphedema and how this relates to cancer and obesity. In addition, we will discuss new therapeutic strategies to treat lymphedema. Finally, we will address the prospects of lymphedema research in the context of the microenvironment.
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Affiliation(s)
- Lazina Hossain
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada
| | - Karina P Gomes
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada
| | - Samaneh Safarpour
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada
| | - Spencer B Gibson
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada.
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2
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Zhang JY, Li H, Zhang MJ, Sun ZJ. Lymphangiogenesis orchestrating tumor microenvironment: Face changing in immunotherapy. Biochim Biophys Acta Rev Cancer 2025; 1880:189278. [PMID: 39929379 DOI: 10.1016/j.bbcan.2025.189278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 01/22/2025] [Accepted: 02/04/2025] [Indexed: 02/19/2025]
Abstract
In the era of immunotherapy, the lymphatic system has garnered significant attention from researchers. Increasing evidence highlights the complex regulation of lymphatic vessels (LVs) within the tumor microenvironment, unveiling a paradox in tumor progression: while LVs enhance immune surveillance, they simultaneously foster immune suppression. This review summarizes the regulatory factors of lymphangiogenesis, discusses the intricate effects of LVs on immunotherapy, and emphasizes the potential connection between lymphangiogenesis and tertiary lymphoid structure. Additionally, current therapeutic strategies targeting lymphangiogenesis are critically evaluated, with a forward-looking perspective on future research directions and regulatory approaches to achieve precise targeting and optimize immunotherapy paradigms.
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Affiliation(s)
- Jun-Ye Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Centre for Immunology and Metabolism, Taikang Centre for Life and Medical Sciences, Wuhan University, Wuhan 430079, China
| | - Hao Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Centre for Immunology and Metabolism, Taikang Centre for Life and Medical Sciences, Wuhan University, Wuhan 430079, China; Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China
| | - Meng-Jie Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Centre for Immunology and Metabolism, Taikang Centre for Life and Medical Sciences, Wuhan University, Wuhan 430079, China.
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Centre for Immunology and Metabolism, Taikang Centre for Life and Medical Sciences, Wuhan University, Wuhan 430079, China; Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, China.
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3
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Uemura K, Katayama KI, Nishioka T, Watanabe H, Yamada G, Inoue N, Asamura S. Dynamics of Immune Cell Infiltration and Fibroblast-Derived IL-33/ST2 Axis Induction in a Mouse Model of Post-Surgical Lymphedema. Int J Mol Sci 2025; 26:1371. [PMID: 39941140 PMCID: PMC11818732 DOI: 10.3390/ijms26031371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 02/02/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
Lymphedema is an intractable disease most commonly associated with lymph node dissection for cancer treatment and can lead to a decreased quality of life. Type 2 T helper (Th2) lymphocytes have been shown to be important in the progression of lymphedema. The activation of IL-33 and its receptor, the suppression of tumorigenicity 2 (ST2) signaling pathway, induces the differentiation of Th2 cells, but its involvement in lymphedema remains unclear. In the present study, we analyzed the dynamics of immune cell infiltration, including the IL-33/ST2 axis, in a mouse tail lymphedema model. Neutrophil infiltration was first detected in the lymphedema tissue on postoperative day (POD) 2. Macrophage infiltration increased from POD 2 to 5. The number of CD4+ T cells, including 50% Tregs, gradually increased from POD 14. The mRNA expression of ll13 and Ifng increased on POD 21. The expression of IL-33 was induced in fibroblast nuclei within dermal and subcutaneous tissues from POD 2, and the expression of the Il1rl1 gene encoding ST2 increased from POD 7. We demonstrated the infiltration process from innate to acquired immune cells through the development of a mouse tail lymphedema. The IL-33/ST2 axis was found to be induced during the transition from innate to acquired immunity.
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Affiliation(s)
- Kazuhisa Uemura
- Department of Plastic Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan; (K.U.); (T.N.); (H.W.); (G.Y.); (S.A.)
- Department of Molecular Genetics, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan;
| | - Kei-ichi Katayama
- Department of Molecular Genetics, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan;
| | - Toshihiko Nishioka
- Department of Plastic Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan; (K.U.); (T.N.); (H.W.); (G.Y.); (S.A.)
| | - Hikaru Watanabe
- Department of Plastic Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan; (K.U.); (T.N.); (H.W.); (G.Y.); (S.A.)
| | - Gen Yamada
- Department of Plastic Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan; (K.U.); (T.N.); (H.W.); (G.Y.); (S.A.)
| | - Norimitsu Inoue
- Department of Molecular Genetics, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan;
| | - Shinichi Asamura
- Department of Plastic Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan; (K.U.); (T.N.); (H.W.); (G.Y.); (S.A.)
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Farooq MA, Johnston APR, Trevaskis NL. Impact of nanoparticle properties on immune cell interactions in the lymph node. Acta Biomater 2025; 193:65-82. [PMID: 39701340 DOI: 10.1016/j.actbio.2024.12.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/21/2024] [Accepted: 12/16/2024] [Indexed: 12/21/2024]
Abstract
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.
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Affiliation(s)
- Muhammad Asim Farooq
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia
| | - Angus P R Johnston
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia
| | - Natalie L Trevaskis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia.
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Hammel JH, Arneja A, Cunningham J, Wang M, Schumaecker S, Orihuela YM, Ozulumba T, Zatorski J, Braciale TJ, Luckey CJ, Pompano RR, Munson JM. Engineered human lymph node stroma model for examining interstitial fluid flow and T cell egress. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.03.622729. [PMID: 39677702 PMCID: PMC11642859 DOI: 10.1101/2024.12.03.622729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
The lymph node (LN) performs essential roles in immunosurveillance throughout the body. Developing in vitro models of this key tissue is of great importance to enhancing physiological relevance in immunoengineering. The LN consists of stromal populations and immune cells, which are highly organized and bathed in constant interstitial flow. The stroma, notably the fibroblastic reticular cells (FRCs) and the lymphatic endothelial cells (LECs), play crucial roles in guiding T cell migration and are known to be sensitive to fluid flow. During inflammation, interstitial fluid flow rates drastically increase in the LN. It is unknown how these altered flow rates impact crosstalk and cell behavior in the LN, and most existing in vitro models focus on the interactions between T cells, B cells, and dendritic cells rather than with the stroma. To address this gap, we developed a human engineered model of the LN stroma consisting of FRC-laden hydrogel above a monolayer of LECs in a tissue culture insert with gravity-driven interstitial flow. We found that FRCs had enhanced coverage and proliferation in response to high flow rates, while LECs experienced decreased barrier integrity. We added CD4+ and CD8+ T cells and found that their egress was significantly decreased in the presence of interstitial flow, regardless of magnitude. Interestingly, 3.0 µm/s flow, but not 0.8 µm/s flow, correlated with enhanced inflammatory cytokine secretion in the LN stroma. Overall, we demonstrate that interstitial flow is an essential consideration in the lymph node for modulating LN stroma morphology, T cell migration, and inflammation.
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Yang L, Wang G, Ma Y, Zhao Q, Zhao H, Wang Q, Zhong C, Zhang C, Yang Y. TRPML1 acts as a predisposing factor in lymphedema development by regulating the subcellular localization of aquaporin-3, -5. PLoS One 2024; 19:e0310653. [PMID: 39637010 PMCID: PMC11620549 DOI: 10.1371/journal.pone.0310653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 09/04/2024] [Indexed: 12/07/2024] Open
Abstract
An imbalance in lymphatic fluid, whether it is caused by generation, transport, outflow, or dysfunctional vessels, can lead to lymphedema; however, the exact pathogenesis of this disease remains unclear. To explore the mechanism, we focused on the association among TRPML1, aquaporin-3 (AQP3), and aquaporin-5 (AQP5) in human lymphatic endothelial cells (HLECs). We explored the role of TRPML1 in altering the permeability of HLECs in lymphedema. Meanwhile, we constructed a disease model using gene-knockout mice to observe the effect of TRPML1 on inflammation and fibrosis in lymphedema sites. Our results indicate that TRPML1 not only regulates the localization of AQP3, -5 to the cell membrane but also increases HLEC permeability, disrupts lymphatic fluid transport, and mediates the development of chronic inflammation at the site of lymphedema. Our study suggests that TRPML1 is a precipitating factor in lymphedema. Our findings improve the understanding of TRPML1 and aquaporins in secondary lymphedema, providing valuable insights for future research.
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Affiliation(s)
- Lijie Yang
- Department of Cell Biology and Medical Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Guanzheng Wang
- Department of Cell Biology and Medical Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Yuan Ma
- College of Basic Medicine, Changchun University of Chinese Medicine, Changchun, Jilin Province, China
| | - Qiancheng Zhao
- Department of Cell Biology and Medical Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - He Zhao
- Department of Cell Biology and Medical Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Qi Wang
- Department of Cell Biology and Medical Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Chonghua Zhong
- College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Chunmei Zhang
- Department of Cell Biology and Medical Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
| | - Yiming Yang
- Department of Cell Biology and Medical Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
- College of Basic Medical Sciences, Jilin University, Changchun, Jilin Province, China
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Campbell AC, Kuonqui KG, Ashokan G, Rubin J, Shin J, Pollack BL, Roberts A, Sarker A, Park HJ, Kataru RP, Barrio AV, Mehrara BJ. Role of inducible nitric oxide (iNOS) and nitrosative stress in regulating sex differences in secondary lymphedema. Front Physiol 2024; 15:1510389. [PMID: 39691094 PMCID: PMC11649630 DOI: 10.3389/fphys.2024.1510389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 11/15/2024] [Indexed: 12/19/2024] Open
Abstract
Secondary lymphedema is a common complication following surgical treatment of solid tumors. Although more prevalent in women due to higher breast cancer rates, men also develop lymphedema, often with more severe manifestations. Despite these differences in clinical presentation, the cellular mechanisms underlying sex differences are poorly understood. Previous studies have shown that inducible nitric oxide synthase (iNOS) expression by inflammatory cells is an important regulator of lymphatic pumping and leakiness in lymphedema and that lymphatic endothelial cells are highly sensitive to nitrosative stress. Based on this rationale, we used a mouse tail model of lymphedema to study the role of nitric oxide in sex-related differences in disease severity. Consistent with clinical findings, we found that male mice have significantly worse tail edema and higher rates of tail necrosis compared with female mice following tail skin/lymphatic excision (p = 0.001). Our findings correlated with increased tissue infiltration of iNOS + inflammatory cells, increased iNOS protein expression, and increased nitrosative stress in male mouse lymphedematous skin tissues (p < 0.05). Importantly, transgenic male mice lacking the iNOS gene (iNOS-KO) displayed markedly reduced swelling, inflammation, and tissue necrosis rates, whereas no differences were observed between wild-type and iNOS-KO female mice. Overall, our results indicate that iNOS-mediated nitric oxide production contributes to sex-based differences in secondary lymphedema severity, emphasizing the need to consider sex as a biological variable in lymphedema research.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Raghu P. Kataru
- Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | | | - Babak J. Mehrara
- Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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Wei M, Wang L, Liu X, Deng Y, Yang S, Pan W, Zhang X, Xu G, Xiao S, Deng C. Metformin Eliminates Lymphedema in Mice by Alleviating Inflammation and Fibrosis: Implications for Human Therapy. Plast Reconstr Surg 2024; 154:1128e-1137e. [PMID: 38391208 PMCID: PMC11584190 DOI: 10.1097/prs.0000000000011363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 02/14/2024] [Indexed: 02/24/2024]
Abstract
BACKGROUND Secondary lymphedema is a chronic, disabling disease affecting more than 50% of patients with cancer and lacking effective pharmacologic treatment even for early to middle disease stages. Metformin reportedly exerts anti-inflammatory and antifibrotic effects and is safe, with minimal side effects. The authors investigated the role of metformin in lymphedema mouse models and examined underlying molecular mechanisms. METHODS Male C57BL/6 mice (6 to 8 weeks old; n = 15/group) received metformin (300 mg/kg/day) by gavage on day 3 after lymphedema surgery; saline and sham groups were administered the same volume of saline. Hindlimb circumference and tail volume were monitored every 2 days. On day 28, samples were collected for histologic assessment, Western blotting, and reverse transcription quantitative polymerase chain reaction analysis of inflammation, fibrosis, and AMP-activated protein kinase (AMPK) expression. AMPK activity was assayed in patients with secondary lymphedema (International Society of Lymphology stage II) and controls following strict inclusion criteria. RESULTS Compared with the saline group, the metformin group exhibited hindlimb circumference and tail volume reduced by 469.70% and 305.18%, respectively, on day 28. Dermal thickness was reduced by 38.27% and 72.57% in the hindlimbs and tail, respectively. Metformin decreased CD4+ T-cell infiltration by 19.73%, and decreased expression levels of interleukin-4, interleukin-13, interleukin-17, and transforming growth factor-β1. In addition, it lowered collagen I deposition by 33.18%. Compared with the saline group, the number of lymphatic vessels increased by 229.96% in the metformin group. Both the saline group mice and patients with lymphedema showed reduced AMPK activity; metformin increased p-AMPK expression by 106.12%. CONCLUSION Metformin alleviated inflammation and fibrosis and increased lymphangiogenesis in lymphedema mouse models by activating AMPK signaling. CLINICAL RELEVANCE STATEMENT Metformin provides preliminary evidence as a potential therapeutic option for lymphedema.
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Affiliation(s)
- Miaomiao Wei
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
| | - Liangliang Wang
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
| | - Xin Liu
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
| | - Yaping Deng
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
| | - Sanhong Yang
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
| | - Wenjie Pan
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
| | - Xiaoshan Zhang
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
| | - Guangchao Xu
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University
| | - Shune Xiao
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University
| | - Chengliang Deng
- From the Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University
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Ji RC. The emerging importance of lymphangiogenesis in aging and aging-associated diseases. Mech Ageing Dev 2024; 221:111975. [PMID: 39089499 DOI: 10.1016/j.mad.2024.111975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/17/2024] [Accepted: 07/29/2024] [Indexed: 08/04/2024]
Abstract
Lymphatic aging represented by cellular and functional changes, is involved in increased geriatric disorders, but the intersection between aging and lymphatic modulation is less clear. Lymphatic vessels play an essential role in maintaining tissue fluid homeostasis, regulating immune function, and promoting macromolecular transport. Lymphangiogenesis and lymphatic remodeling following cellular senescence and organ deterioration are crosslinked with the progression of some lymphatic-associated diseases, e.g., atherosclerosis, inflammation, lymphoedema, and cancer. Age-related detrimental tissue changes may occur in lymphatic vessels with diverse etiologies, and gradually shift towards chronic low-grade inflammation, so-called inflammaging, and lead to decreased immune response. The investigation of the relationship between advanced age and organ deterioration is becoming an area of rapidly increasing significance in lymphatic biology and medicine. Here we highlight the emerging importance of lymphangiogenesis and lymphatic remodeling in the regulation of aging-related pathological processes, which will help to find new avenues for effective intervention to promote healthy aging.
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Affiliation(s)
- Rui-Cheng Ji
- Faculty of Welfare and Health Science, Oita University, Oita 870-1192, Japan.
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Jian Y, Li Y, Zhang Y, Tang M, Deng M, Liu C, Cheng M, Xiao S, Deng C, Wei Z. Lymphangiogenesis: novel strategies to promote cutaneous wound healing. BURNS & TRAUMA 2024; 12:tkae040. [PMID: 39328366 PMCID: PMC11427083 DOI: 10.1093/burnst/tkae040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 09/28/2024]
Abstract
The cutaneous lymphatic system regulates tissue inflammation, fluid balance and immunological responses. Lymphangiogenesis or lymphatic dysfunction may lead to lymphedema, immune deficiency, chronic inflammation etc. Tissue regeneration and healing depend on angiogenesis and lymphangiogenesis during wound healing. Tissue oedema and chronic inflammation can slow wound healing due to impaired lymphangiogenesis or lymphatic dysfunction. For example, impaired lymphangiogenesis or lymphatic dysfunction has been detected in nonhealing wounds such as diabetic ulcers, venous ulcers and bedsores. This review summarizes the structure and function of the cutaneous lymphatic vessel system and lymphangiogenesis in wounds. Furthermore, we review wound lymphangiogenesis processes and remodelling, especially the influence of the inflammatory phase. Finally, we outline how to control lymphangiogenesis to promote wound healing, assess the possibility of targeting lymphangiogenesis as a novel treatment strategy for chronic wounds and provide an analysis of the possible problems that need to be addressed.
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Affiliation(s)
- Yang Jian
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Yanqi Li
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Yanji Zhang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Mingyuan Tang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Mingfu Deng
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Chenxiaoxiao Liu
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Maolin Cheng
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
| | - Shune Xiao
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, No. 6 West Xuefu Road, Xinpu District, Zunyi, Guizhou, 563003, China
| | - Chengliang Deng
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, No. 6 West Xuefu Road, Xinpu District, Zunyi, Guizhou, 563003, China
| | - Zairong Wei
- Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, No. 149 Dalian Road, Hui chuan District, Zunyi, Guizhou, 563003, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, No. 6 West Xuefu Road, Xinpu District, Zunyi, Guizhou, 563003, China
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Michalaki E, Chin R, Jeong K, Qi Z, Liebman LN, González-Vargas Y, Echeverri ES, Paunovska K, Muramatsu H, Pardi N, Tamburini BJ, Jakus Z, Dahlman JE, Dixon JB. Lymphatic endothelial cell-targeting lipid nanoparticles delivering VEGFC mRNA improve lymphatic function after injury. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.31.605343. [PMID: 39131391 PMCID: PMC11312618 DOI: 10.1101/2024.07.31.605343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/13/2024]
Abstract
Dysfunction of the lymphatic system following injury, disease, or cancer treatment can lead to lymphedema, a debilitating condition with no cure. Advances in targeted therapy have shown promise for treating diseases where conventional therapies have been ineffective and lymphatic vessels have recently emerged as a new therapeutic target. Lipid nanoparticles (LNPs) have emerged as a promising strategy for tissue specific delivery of nucleic acids. Currently, there are no approaches to target LNPs to lymphatic endothelial cells, although it is well established that intradermal (ID) injection of nanoparticles will drain to lymphatics with remarkable efficiency. To design an LNP that would effectively deliver mRNA to LEC after ID delivery, we screened a library of 150 LNPs loaded with a reporter mRNA, for both self-assembly and delivery in vivo to lymphatic endothelial cells (LECs). We identified and validated several LNP formulations optimized for high LEC uptake when administered ID and compared their efficacy for delivery of functional mRNA with that of free mRNA and mRNA delivered with a commercially available MC3-based LNP (Onpattro™). The lead LEC-specific LNP was then loaded with VEGFC mRNA to test the therapeutic advantage of the LEC-specific LNP (namely, LNP7) for treating a mouse tail lymphatic injury model. A single dose of VEGFC mRNA delivered via LNP7 resulted in enhanced LEC proliferation at the site of injury, and an increase in lymphatic function up to 14-days post-surgery. Our results suggest a therapeutic potential of VEGFC mRNA lymphatic-specific targeted delivery in alleviating lymphatic dysfunction observed during lymphatic injury and could provide a promising approach for targeted, transient lymphangiogenic therapy.
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Affiliation(s)
- Eleftheria Michalaki
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology; Atlanta, GA, USA
| | - Rachel Chin
- Department of Biology, Georgia Institute of Technology; Atlanta, GA, USA
| | - Kiyoung Jeong
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University; Atlanta, GA, USA
| | - Zhiming Qi
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University; Atlanta, GA, USA
| | - Lauren N. Liebman
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University; Atlanta, GA, USA
| | - Yarelis González-Vargas
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University; Atlanta, GA, USA
| | - Elisa Schrader Echeverri
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University; Atlanta, GA, USA
| | - Kalina Paunovska
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University; Atlanta, GA, USA
| | - Hiromi Muramatsu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, USA
| | - Norbert Pardi
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania; Philadelphia, PA, USA
| | - Beth Jiron Tamburini
- University of Colorado School of Medicine, Department of Medicine, Aurora, CO, USA
| | - Zoltan Jakus
- Semmelweis University School of Medicine, Department of Physiology, Budapest, Hungary
| | - James E. Dahlman
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University; Atlanta, GA, USA
| | - J. Brandon Dixon
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology; Atlanta, GA, USA
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University; Atlanta, GA, USA
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology; Atlanta, GA, USA
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12
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Hossain L, Gomes KP, Yang X, Liu E, Du Toit J, von der Weid PY, Gibson SB. Vascular Endothelial Growth Factor C (VEGF-C) Sensitizes Lymphatic Endothelial Cells to Oxidative-Stress-Induced Apoptosis through DNA Damage and Mitochondrial Dysfunction: Implications for Lymphedema. Int J Mol Sci 2024; 25:7828. [PMID: 39063073 PMCID: PMC11277328 DOI: 10.3390/ijms25147828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/05/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Secondary lymphedema is caused by damage to the lymphatic system from surgery, cancer treatment, infection, trauma, or obesity. This damage induces stresses such as oxidative stress and hypoxia in lymphatic tissue, impairing the lymphatic system. In response to damage, vascular endothelial growth factor C (VEGF-C) levels increase to induce lymphangiogenesis. Unfortunately, VEGF-C often fails to repair the lymphatic damage in lymphedema. The underlying mechanism contributing to lymphedema is not well understood. In this study, we found that surgery-induced tail lymphedema in a mouse model increased oxidative damage and cell death over 16 days. This corresponded with increased VEGF-C levels in mouse tail lymphedema tissue associated with macrophage infiltration. Similarly, in the plasma of patients with secondary lymphedema, we found a positive correlation between VEGF-C levels and redox imbalance. To determine the effect of oxidative stress in the presence or absence of VEGF-C, we found that hydrogen peroxide (H2O2) induced cell death in human dermal lymphatic endothelial cells (HDLECs), which was potentiated by VEGF-C. The cell death induced by VEGF-C and H2O2 in HDLECs was accompanied by increased reactive oxygen species (ROS) levels and a loss of mitochondrial membrane potential. Antioxidant pre-treatment rescued HDLECs from VEGF-C-induced cell death and decreased ROS under oxidative stress. As expected, VEGF-C increased the number of viable and proliferating HDLECs. However, upon H2O2 treatment, VEGF-C failed to increase either viable or proliferating cells. Since oxidative stress leads to DNA damage, we also determined whether VEGF-C treatment induces DNA damage in HDLECs undergoing oxidative stress. Indeed, DNA damage, detected in the form of gamma H2AX (γH2AX), was increased by VEGF-C under oxidative stress. The potentiation of oxidative stress damage induced by VEFG-C in HDLECs was associated with p53 activation. Finally, the inhibition of vascular endothelial growth factor receptor-3 (VEGFR-3) activation blocked VEGF-C-induced cell death following H2O2 treatment. These results indicate that VEGF-C further sensitizes lymphatic endothelial cells to oxidative stress by increasing ROS and DNA damage, potentially compromising lymphangiogenesis.
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Affiliation(s)
- Lazina Hossain
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (L.H.); (K.P.G.); (X.Y.); (E.L.); (J.D.T.)
| | - Karina Pereira Gomes
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (L.H.); (K.P.G.); (X.Y.); (E.L.); (J.D.T.)
| | - Xiaoyan Yang
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (L.H.); (K.P.G.); (X.Y.); (E.L.); (J.D.T.)
| | - Emily Liu
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (L.H.); (K.P.G.); (X.Y.); (E.L.); (J.D.T.)
| | - Jacques Du Toit
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (L.H.); (K.P.G.); (X.Y.); (E.L.); (J.D.T.)
| | - Pierre-Yves von der Weid
- Department of Physiology & Pharmacology, Inflammation Research Network, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T6G 2R3, Canada;
| | - Spencer Bruce Gibson
- Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada; (L.H.); (K.P.G.); (X.Y.); (E.L.); (J.D.T.)
- Department of Physiology & Pharmacology, Inflammation Research Network, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB T6G 2R3, Canada;
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13
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Lee SO, Kim IK. Molecular pathophysiology of secondary lymphedema. Front Cell Dev Biol 2024; 12:1363811. [PMID: 39045461 PMCID: PMC11264244 DOI: 10.3389/fcell.2024.1363811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 06/20/2024] [Indexed: 07/25/2024] Open
Abstract
Lymphedema occurs as a result of lymphatic vessel damage or obstruction, leading to the lymphatic fluid stasis, which triggers inflammation, tissue fibrosis, and adipose tissue deposition with adipocyte hypertrophy. The treatment of lymphedema is divided into conservative and surgical approaches. Among surgical treatments, methods like lymphaticovenular anastomosis and vascularized lymph node transfer are gaining attention as they focus on restoring lymphatic flow, constituting a physiologic treatment approach. Lymphatic endothelial cells form the structure of lymphatic vessels. These cells possess button-like junctions that facilitate the influx of fluid and leukocytes. Approximately 10% of interstitial fluid is connected to venous return through lymphatic capillaries. Damage to lymphatic vessels leads to lymphatic fluid stasis, resulting in the clinical condition of lymphedema through three mechanisms: Inflammation involving CD4+ T cells as the principal contributing factor, along with the effects of immune cells on the VEGF-C/VEGFR axis, consequently resulting in abnormal lymphangiogenesis; adipocyte hypertrophy and adipose tissue deposition regulated by the interaction of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor-γ; and tissue fibrosis initiated by the overactivity of Th2 cells, leading to the secretion of profibrotic cytokines such as IL-4, IL-13, and the growth factor TGF-β1. Surgical treatments aimed at reconstructing the lymphatic system help facilitate lymphatic fluid drainage, but their effectiveness in treating already damaged lymphatic vessels is limited. Therefore, reviewing the pathophysiology and molecular mechanisms of lymphedema is crucial to complement surgical treatments and explore novel therapeutic approaches.
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Anurogo D, Luthfiana D, Anripa N, Fauziah AI, Soleha M, Rahmah L, Ratnawati H, Wargasetia TL, Pratiwi SE, Siregar RN, Sholichah RN, Maulana MS, Ikrar T, Chang YH, Qiu JT. The Art of Bioimmunogenomics (BIGs) 5.0 in CAR-T Cell Therapy for Lymphoma Management. Adv Pharm Bull 2024; 14:314-330. [PMID: 39206402 PMCID: PMC11347730 DOI: 10.34172/apb.2024.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 01/13/2024] [Accepted: 03/03/2024] [Indexed: 09/04/2024] Open
Abstract
Purpose Lymphoma, the most predominant neoplastic disorder, is divided into Hodgkin and Non-Hodgkin Lymphoma classifications. Immunotherapeutic modalities have emerged as essential methodologies in combating lymphoid malignancies. Chimeric Antigen Receptor (CAR) T cells exhibit promising responses in chemotherapy-resistant B-cell non-Hodgkin lymphoma cases. Methods This comprehensive review delineates the advancement of CAR-T cell therapy as an immunotherapeutic instrument, the selection of lymphoma antigens for CAR-T cell targeting, and the conceptualization, synthesis, and deployment of CAR-T cells. Furthermore, it encompasses the advantages and disadvantages of CAR-T cell therapy and the prospective horizons of CAR-T cells from a computational research perspective. In order to improve the design and functionality of artificial CARs, there is a need for TCR recognition investigation, followed by the implementation of a quality surveillance methodology. Results Various lymphoma antigens are amenable to CAR-T cell targeting, such as CD19, CD20, CD22, CD30, the kappa light chain, and ROR1. A notable merit of CAR-T cell therapy is the augmentation of the immune system's capacity to generate tumoricidal activity in patients exhibiting chemotherapy-resistant lymphoma. Nevertheless, it also introduces manufacturing impediments that are laborious, technologically demanding, and financially burdensome. Physical, physicochemical, and physiological limitations further exacerbate the challenge of treating solid neoplasms with CAR-T cells. Conclusion While the efficacy and safety of CAR-T cell immunotherapy remain subjects of fervent investigation, the promise of this cutting-edge technology offers valuable insights for the future evolution of lymphoma treatment management approaches. Moreover, CAR-T cell therapies potentially benefit patients, motivating regulatory bodies to foster international collaboration.
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Affiliation(s)
- Dito Anurogo
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Faculty of Medicine and Health Sciences, Muhammadiyah University of Makassar, Makassar, South Sulawesi, 90221, Indonesia
| | - Dewi Luthfiana
- Bioinformatics Research Center, Indonesian Institute of Bioinformatics (INBIO), Malang, East Java, 65162, Indonesia
| | - Nuralfin Anripa
- Department of Environmental Science, Dumoga University, Kotamobagu, South Sulawesi, 95711, Indonesia
- Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Apriliani Ismi Fauziah
- MSc Program in Tropical Medicine, Kaohsiung Medical University, Kaohsiung City, 807378, Taiwan
| | - Maratu Soleha
- National Research and Innovation Agency (BRIN), Central Jakarta, 10340, Indonesia
- IKIFA College of Health Sciences, East Jakarta, Special Capital Region of Jakarta, 13470, Indonesia
| | - Laila Rahmah
- Department of Digital Health, School of Medicine, Tehran University of Medical Sciences, Tehran, 1416634793, Iran
- Faculty of Medicine, Muhammadiyah University of Surabaya, Surabaya, East Java, 60113, Indonesia
| | - Hana Ratnawati
- Faculty of Medicine, Maranatha Christian University, Bandung, West Java, 40164, Indonesia
| | | | - Sari Eka Pratiwi
- Department of Biology and Pathobiology, Faculty of Medicine, Tanjungpura University, Pontianak, West Kalimantan, 78115, Indonesia
| | - Riswal Nafi Siregar
- National Research and Innovation Agency (BRIN), Central Jakarta, 10340, Indonesia
| | - Ratis Nour Sholichah
- Department of Biotechnology, Postgraduate School of Gadjah Mada University, Yogyakarta, 55284, Indonesia
| | - Muhammad Sobri Maulana
- Community Health Center (Puskesmas) Temon 1, Kulon Progo, Special Region of Yogyakarta, 55654, Indonesia
| | - Taruna Ikrar
- Director of Members-at-Large, International Association of Medical Regulatory Authorities (IAMRA), Texas, 76039, USA
- Aivita Biomedical Inc., Irvine, California, 92612, USA
- Chairman of Medical Council, The Indonesian Medical Council (KKI), Central Jakarta, 10350, Indonesia
- Adjunct Professor, School of Military Medicine, The Republic of Indonesia Defense University (RIDU), Jakarta Pusat, 10440, Indonesia
- Department of Pharmacology, Faculty of Medicine, Malahayati University, Bandar Lampung, Lampung, 35152, Indonesia
| | - Yu Hsiang Chang
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Locus Cell Co., LTD., Xizhi Dist., New Taipei City, 221, Taiwan
| | - Jiantai Timothy Qiu
- International Ph.D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110301, Taiwan
- Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, 110301, Taiwan
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15
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Aimaitijiang Y, Jiang TM, Shao YM, Aji T. Fifty-five cases of hepatic alveolar echinococcosis combined with lymph node metastasis: A retrospective study. World J Gastroenterol 2024; 30:2981-2990. [PMID: 38946870 PMCID: PMC11212701 DOI: 10.3748/wjg.v30.i23.2981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 05/02/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Lymph node metastasis is a specific type of metastasis in hepatic alveolar echinococcosis (AE). Currently, there is a scarcity of describing the clinical characteristics and lymph node metastasis rules of patients with hepatic AE combined with lymph node metastasis and its mechanism and management are still controversial. Radical hepatectomy combined with regional lymph node dissection is a better treatment. AIM To analyse the clinical features of hepatic AE combined with lymph node metastasis to explore its treatment and efficacy. METHODS A total of 623 patients with hepatic AE admitted to the First Affiliated Hospital of Xinjiang Medical University from 1 January 2012 to 1 January 2022 were retrospectively analysed. Fifty-five patients with combined lymph node metastasis were analysed for their clinical data, diagnosis and treatment methods, follow-up efficacy, and characteristics of lymph node metastasis. Finally, we comparatively analysed the lymph node metastasis rates at different sites. Categorical variables are expressed as frequencies and percentages, and the analysis of difference was performed using the χ 2 test. The Bonferroni method was used for pairwise comparisons when statistical differences existed between multiple categorical variables. RESULTS A lymph node metastasis rate of 8.8% (55/623) was reported in patients with hepatic AE, with a female predilection (69.1%) and a statistically significant sex difference (χ 2 = 8.018, P = 0.005). Of the 55 patients with lymph node metastasis, 72.7% had a parasite lesion, neighbouring organ invasion, and metastasis stage of P3N1M0 and above, of which 67.3%, 78.2%, and 34.5% of hepatic AE lesions invaded the bile ducts, blood vessels, and distant metastases, respectively. Detection rates of lymph node metastasis of 16.4%, 21.7%, and 34.2% were reported for a preoperative abdominal ultrasound, magnetic resonance imaging, and computed tomography examinations. All patients were intraoperatively suspected with enlarged lymph nodes and underwent radical hepatectomy combined with regional lymph node dissection. After surgery, a routine pathological examination was conducted on the resected lymph nodes. A total of 106 positive lymph nodes were detected in six groups at various sites, including 51 single-group metastasis cases and four multi-group metastasis cases. When the metastasis rates at different sites were statistically analysed, we observed that the metastasis rate in the para-hepatoduodenal ligament lymph nodes was significantly higher than that of the other sites (χ 2 = 128.089, P = 0.000 < 0.05). No statistical difference was observed in the metastasis rate between the five other groups. Clavien-Dindo grade IIIa complication occurred in 14 cases, which improved after administering symptomatic treatment. Additionally, lymph node dissection-related complications were not observed. Recurrence after 2 years was observed in one patient. CONCLUSION Lymph node metastasis is a rare form of metastasis in hepatic AE, which is more frequent in women. Para-hepatoduodenal ligament lymph nodes are commonly observed. Radical hepatectomy combined with regional lymph node dissection is a safe, effective, and feasible treatment for liver AE combined with lymph node metastasis.
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Affiliation(s)
- Yilizhati Aimaitijiang
- State Key Laboratory on Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, The First Clinical College, Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China
- The First Ward of Hepatobiliary and Pancreatic Surgery, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi 830011, Xinjiang Uygur Autonomous Region, China
| | - Tie-Min Jiang
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
| | - Ying-Mei Shao
- Xinjiang Clinical Research Center for Echinococcosis and Hepatobiliary Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
| | - Tuerganaili Aji
- Department of Hepatobiliary & Hydatid Diseases, Digestive & Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, Xinjiang Uygur Autonomous Region, China
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16
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Fowler JWM, Song L, Tam K, Roth Flach RJ. Targeting lymphatic function in cardiovascular-kidney-metabolic syndrome: preclinical methods to analyze lymphatic function and therapeutic opportunities. Front Cardiovasc Med 2024; 11:1412857. [PMID: 38915742 PMCID: PMC11194411 DOI: 10.3389/fcvm.2024.1412857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 05/24/2024] [Indexed: 06/26/2024] Open
Abstract
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.
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Affiliation(s)
| | | | | | - Rachel J. Roth Flach
- Internal Medicine Research Unit, Pfizer Research and Development, Cambridge, MA, United States
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17
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Yang W. Comprehensive analysis of the clinical manifestations and hematological parameters associated with secondary immune thrombocytopenia in patients with primary Sjögren syndrome: An observational study. Medicine (Baltimore) 2024; 103:e37909. [PMID: 38728456 PMCID: PMC11081593 DOI: 10.1097/md.0000000000037909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/25/2024] [Indexed: 05/12/2024] Open
Abstract
Primary Sjögren Syndrome (pSS) is a chronic autoimmune disease that primarily affects exocrine glands and can lead to various extraglandular manifestations, including secondary immune thrombocytopenia (ITP). Understanding the clinical and hematological differences in pSS patients with and without secondary ITP is crucial for improved patient management and treatment strategies. This retrospective study, conducted from January 2020 to December 2023, involved a cohort of pSS patients, dividing them into 2 groups: those with secondary ITP and those without. Patients were evaluated using the European League Against Rheumatism Sjögren Syndrome Disease Activity Index (ESSDAI), EULAR Sjögren Syndrome Patient-Reported Index (ESSPRI), Health Assessment Questionnaire, and other hematological parameters. Inclusion criteria were based on the American-European Consensus Group or ACR/EULAR classification criteria for pSS. Exclusion criteria included other autoimmune or hematological disorders, prior splenectomy, recent blood transfusions, and lack of informed consent. Statistical analysis was performed using SPSS software, with various tests applied to analyze the data, including logistic regression to identify risk factors for secondary ITP. Significant differences were noted in fatigue, lymphadenopathy, arthritis, mean age, and ESSDAI scores between the secondary ITP and non-secondary ITP groups. Patients with secondary ITP exhibited higher platelet counts, more prevalent lymphopenia, higher immunoglobulin G (IgG) levels, lower complement 3 levels, and reduced white blood cell and hemoglobin levels. Logistic regression analysis identified lymphadenopathy as a risk factor and arthritis as a protective factor for the development of secondary ITP. The study reveals distinct clinical and hematological characteristics in pSS patients with secondary ITP, suggesting a higher disease activity in this subset. These findings underscore the need for further exploration of these associations to develop more precise treatment approaches for pSS, focusing on preventing secondary ITP and improving patient outcomes.
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Affiliation(s)
- Wenwen Yang
- Department of Medical Nursing, Cangzhou Medical College, Cangzhou, Hebei Province, China
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18
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Miaskowski C, Conley YP, Cooper BA, Paul SM, Smoot BJ, Hammer MJ, Fu M, Levine JD. Identification Of A Higher Risk Lymphedema Phenotype And Associations With Cytokine Gene Polymorphisms. J Pain Symptom Manage 2024; 67:375-383.e3. [PMID: 38307372 DOI: 10.1016/j.jpainsymman.2024.01.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/21/2024] [Accepted: 01/24/2024] [Indexed: 02/04/2024]
Abstract
CONTEXT Breast cancer-related lymphedema (BCRL) is chronic condition that occurs in 5% to 75% of women following treatment for breast cancer. However, little is known about the risk factors and mechanisms associated with a worse BCRL profile. OBJECTIVES Identify distinct BCRL profiles in women with the condition (i.e., lower vs. higher risk phenotype) and evaluate for associations with pro- and anti-inflammatory genes. METHODS Latent class profile analysis (LCPA) was used to identify the BCRL profiles using phenotypic characteristics evaluated prior to surgery. Candidate gene analyses were done to identify cytokine genes associated with the two BCRL profiles. RESULTS Of the 155 patients evaluated, 35.5% (n = 55) were in the Lower and 64.5% (n = 100) were in the Higher Risk classes. Risk factors for membership in the Higher class included: lower functional status, having sentinel lymph node biopsy, axillary lymph node dissection, mastectomy, higher number of positive lymph nodes, and receipt of chemotherapy. Polymorphisms for interleukin (IL)1-beta and IL6 were associated with membership in the Higher Risk class. CONCLUSION The readily available and clinically relevant phenotypic characteristics associated with a worse BCRL profile can be used by clinicians to identify higher risk patients. If confirmed, these characteristics can be tested in predictive risk models. In addition, the candidate gene findings may guide the development of mechanistically-based interventions to decrease the risk of BCRL.
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Affiliation(s)
- Christine Miaskowski
- School of Nursing, University of California, San Francisco, CA, USA; School of Medicine, University of California, San Francisco, CA, USA.
| | | | - Bruce A Cooper
- School of Nursing, University of California, San Francisco, CA, USA
| | - Steven M Paul
- School of Nursing, University of California, San Francisco, CA, USA
| | - Betty J Smoot
- School of Medicine, University of California, San Francisco, CA, USA
| | | | - Mei Fu
- School of Nursing and Health Studies, University of Missouri, Kansas City, MO, USA
| | - Jon D Levine
- School of Medicine, University of California, San Francisco, CA, USA
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19
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Bowman C, Rockson SG. The Role of Inflammation in Lymphedema: A Narrative Review of Pathogenesis and Opportunities for Therapeutic Intervention. Int J Mol Sci 2024; 25:3907. [PMID: 38612716 PMCID: PMC11011271 DOI: 10.3390/ijms25073907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/20/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Lymphedema is a chronic and progressive disease of the lymphatic system characterized by inflammation, increased adipose deposition, and tissue fibrosis. Despite early hypotheses identifying lymphedema as a disease of mechanical lymphatic disruption alone, the progressive inflammatory nature underlying this condition is now well-established. In this review, we provide an overview of the various inflammatory mechanisms that characterize lymphedema development and progression. These mechanisms contribute to the acute and chronic phases of lymphedema, which manifest clinically as inflammation, fibrosis, and adiposity. Furthermore, we highlight the interplay between current therapeutic modalities and the underlying inflammatory microenvironment, as well as opportunities for future therapeutic development.
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Affiliation(s)
- Catharine Bowman
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA;
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Stanley G. Rockson
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA;
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20
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Aradi P, Kovács G, Kemecsei É, Molnár K, Sági SM, Horváth Z, Mehrara BJ, Kataru RP, Jakus Z. Lymphatic-Dependent Modulation of the Sensitization and Elicitation Phases of Contact Hypersensitivity. J Invest Dermatol 2024:S0022-202X(24)00261-6. [PMID: 38548256 DOI: 10.1016/j.jid.2024.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 02/17/2024] [Accepted: 03/01/2024] [Indexed: 05/26/2024]
Abstract
Allergic contact dermatitis is a common inflammatory skin disease comprising 2 phases. During sensitization, immune cells are activated by exposure to various allergens, whereas repeated antigen exposure induces local inflammation during elicitation. In this study, we utilized mouse models lacking lymphatics in different skin regions to characterize the role of lymphatics separately in the 2 phases, using contact hypersensitivity as a model of human allergic inflammatory skin diseases. Lymphatic-deficient mice exhibited no major difference to single antigen exposure compared to controls. However, mice lacking lymphatics in both phases displayed reduced inflammation after repeated antigen exposure. Similarly, diminished immune response was observed in mice lacking lymphatics only in sensitization, whereas the absence of lymphatics only in the elicitation phase resulted in a more pronounced inflammatory immune response. This exaggerated inflammation is driven by neutrophils impacting regulatory T cell number. Collectively, our results demonstrate that skin lymphatics play an important but distinct role in the 2 phases of contact hypersensitivity. During sensitization, lymphatics contribute to the development of the antigen-specific immunization, whereas in elicitation, they moderate the inflammatory response and leukocyte infiltration in a neutrophil-dependent manner. These findings underscore the need for novel therapeutic strategies targeting the lymphatics in the context of allergic skin diseases.
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Affiliation(s)
- Petra Aradi
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Gábor Kovács
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Éva Kemecsei
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Kornél Molnár
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Stella Márta Sági
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Zalán Horváth
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary
| | - Babak J Mehrara
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Raghu P Kataru
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Zoltán Jakus
- Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.
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21
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McCright J, Yarmovsky J, Maisel K. Para- and Transcellular Transport Kinetics of Nanoparticles across Lymphatic Endothelial Cells. Mol Pharm 2024; 21:1160-1169. [PMID: 37851841 PMCID: PMC10923144 DOI: 10.1021/acs.molpharmaceut.3c00720] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2023]
Abstract
Lymphatic vessels have received significant attention as drug delivery targets, as they shuttle materials from peripheral tissues to the lymph nodes, where adaptive immunity is formed. Delivery of immune modulatory materials to the lymph nodes via lymphatic vessels has been shown to enhance their efficacy and also improve the bioavailability of drugs when delivered to intestinal lymphatic vessels. In this study, we generated a three-compartment model of a lymphatic vessel with a set of kinematic differential equations to describe the transport of nanoparticles from the surrounding tissues into lymphatic vessels. We used previously published data and collected additional experimental parameters, including the transport efficiency of nanoparticles over time, and also examined how nanoparticle formulation affected the cellular transport mechanisms using small molecule inhibitors. These experimental data were incorporated into a system of kinematic differential equations, and nonlinear, least-squares curve fitting algorithms were employed to extrapolate transport coefficients within our model. The subsequent computational framework produced some of the first parameters to describe transport kinetics across lymphatic endothelial cells and allowed for the quantitative analysis of the driving mechanisms of transport into lymphatic vessels. Our model indicates that transcellular mechanisms, such as micro- and macropinocytosis, drive transport into lymphatics. This information is crucial to further design strategies that will modulate lymphatic transport for drug delivery, particularly in diseases like lymphedema, where normal lymphatic functions are impaired.
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Affiliation(s)
- Jacob McCright
- Department of Bioengineering, University of Maryland College Park, College Park, Maryland 20742, United States
| | - Jenny Yarmovsky
- Department of Bioengineering, University of Maryland College Park, College Park, Maryland 20742, United States
| | - Katharina Maisel
- Department of Bioengineering, University of Maryland College Park, College Park, Maryland 20742, United States
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22
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Surtani S, Kailashiya J, Ansari MA, Dash D, Yadav AK, Kumar A. Platelet functions in lymphatic filariasis patients. Microvasc Res 2024; 152:104642. [PMID: 38070864 DOI: 10.1016/j.mvr.2023.104642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 11/27/2023] [Accepted: 12/03/2023] [Indexed: 02/03/2024]
Abstract
Filariasis is a chronic disease where parasitic worms survive in human hosts even for decades and lead to complications like lymphedema and elephantiasis. Despite the persistent existence of filarial parasites in human hosts, fatal and thrombotic complications are not known, unlike other parasitic diseases like malaria. This suggests that filarial parasites might be affecting the host's platelet functions. This study was conducted to examine platelet functions in confirmed filariasis patients and healthy controls. Results showed that filariasis patients had larger platelets, inhibited aggregation, and slower speed of aggregation, compared to controls. However, in vivo markers of platelet activation and degranulation (beta thromboglobulin and soluble P-selectin) were not affected. Observations suggested that there is increased platelet turnover, cellular apoptosis and inhibited platelet functions in filariasis patients compared to controls. Platelet function inhibition was not associated with the duration of disease, lymphedema-affected organs, or gender of patients. This study confirms that filarial parasites modulate platelet functions in human hosts.
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Affiliation(s)
- Sushil Surtani
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Jyotsna Kailashiya
- Centre for Advanced Research on Platelet Signaling & Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
| | - Mumtaz Ahmad Ansari
- Department of General Surgery, Sir Sundarlal Hospital, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Debabrata Dash
- Centre for Advanced Research on Platelet Signaling & Thrombosis Biology, Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Awadesh Kumar Yadav
- National Centre for Disease Control, Ministry of Health and Family Welfare, Varanasi, Uttar Pradesh, India
| | - Ashutosh Kumar
- Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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23
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Cąkała-Jakimowicz M, Domaszewska-Szostek A, Puzianowska-Kuznicka M. Interruption of Lymph Flow Worsens the Skin Inflammation Caused by Saprophytic Staphylococcus epidermidis. Biomedicines 2023; 11:3234. [PMID: 38137455 PMCID: PMC10740757 DOI: 10.3390/biomedicines11123234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/28/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
Lymphedema is often complicated by chronic inflammation, leading to fibrosis, fat deposition, and inhibition of lymphangiogenesis. This study aimed to verify whether lymphedema itself or together with commensal bacterial flora infection contributes to the severity of local inflammation. Edema was induced by interruption of the lymph flow in the rat's hind limb. Immune cell infiltrates were examined by flow cytometry and immunohistochemistry. Nine-day edema alone did not affect immune cell content in the skin but resulted in a decrease in CD4+ T helper lymphocytes and monocytes in the draining popliteal lymph nodes. In turn, local saprophytic Staphylococcus epidermidis infection of the edematous limb resulted in dense infiltrates of CD68+ macrophages and monocytes, MHC class II antigen-presenting cells, CD90+ stem cells, thymocytes, and immature B cells in the skin, accompanied by a simultaneous reduction in density of CD4+ T helper lymphocytes and monocytes, OX62+ dendritic cells, CD68+ macrophages and monocytes, HiS48+ granulocytes, CD90+ stem cells, thymocytes, and immature B cells in the draining popliteal lymph nodes. These results indicate that the combination of edema and saprophytic bacteria infection induces severe inflammation in the peripheral tissues and results in a delay of antibacterial protection processes in neighboring lymphatic organs.
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Affiliation(s)
- Marta Cąkała-Jakimowicz
- Department of Human Epigenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland;
| | - Anna Domaszewska-Szostek
- Department of Human Epigenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland;
| | - Monika Puzianowska-Kuznicka
- Department of Human Epigenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland;
- Department of Geriatrics and Gerontology, Medical Centre of Postgraduate Education, 01-813 Warsaw, Poland
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24
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Pearce J, Hadcocks L, Mansour S, van Zanten M, Jeffery S, Gordon K, Ostergaard P, Mortimer P, Macallan DC. Profound and selective lymphopaenia in primary lymphatic anomaly patients demonstrates the significance of lymphatic-lymphocyte interactions. Front Immunol 2023; 14:1279077. [PMID: 38022535 PMCID: PMC10656747 DOI: 10.3389/fimmu.2023.1279077] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction The lymphatic system has a pivotal role in immune homeostasis. To better understand this, we investigated the impact of Primary Lymphatic Anomalies (PLA) on lymphocyte numbers and phenotype. Methods The study comprised (i) a retrospective cohort: 177 PLA subjects from the National Primary Lymphatic Anomaly Register with clinical and laboratory data, and (ii) a prospective cohort: 28 patients with PLA and 20 healthy controls. Patients were subdivided using established phenotypic diagnostic categories and grouped into simplex (localised tissue involvement only) and systemic (involvement of central lymphatics). Further grouping variables included genital involvement and the likelihood of co-existent intestinal lymphangiectasia. Haematology laboratory parameters were analysed in both cohorts. In the prospective cohort, prospective blood samples were analysed by flow cytometry for markers of proliferation, differentiation, activation, skin-homing, and for regulatory (CD4+Foxp3+) T cells (Treg). Results In patients with PLA, lymphopaenia was frequent (22% of subjects), affected primarily the CD4+ T cell subset, and was more severe in subjects with systemic versus simplex patterns of disease (36% vs 9% for lymphopaenia; 70% vs 33% for CD4+ cells). B cells, NK cells and monocytes were better conserved (except in GATA2 deficiency characterised by monocytopaenia). Genital oedema and likelihood of concomitant intestinal lymphangiectasia independently predicted CD4+ T cell depletion. Analysing CD4+ and CD8+ T cells by differentiation markers revealed disproportionate depletion of naïve cells, with a skewing towards a more differentiated effector profile. Systemic PLA conditions were associated with: increased expression of Ki67, indicative of recent cell division, in naïve CD4+, but not CD8+ T cells; increased levels of activation in CD4+, but not CD8+ T cells; and an increased proportion of Treg. Skin-homing marker (CCR10, CLA and CCR4) expression was reduced in some patients with simplex phenotypes. Discussion Patients with PLA who have dysfunctional lymphatics have a selective reduction in circulating lymphocytes which preferentially depletes naïve CD4+ T cells. The presence of systemic disease, genital oedema, and intestinal lymphangiectasia independently predict CD4 lymphopaenia. The association of this depletion with immune activation and increased circulating Tregs suggests lymphatic-lymphocyte interactions and local inflammatory changes are pivotal in driving immunopathology.
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Affiliation(s)
- Julian Pearce
- Lymphovascular Research Unit, Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, United Kingdom
- Dermatology and Lymphovascular Medicine, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
| | - Linda Hadcocks
- Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
| | - Sahar Mansour
- Lymphovascular Research Unit, Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, United Kingdom
- Dermatology and Lymphovascular Medicine, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
- South West Thames Regional Centre for Genomics, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
| | - Malou van Zanten
- Lymphovascular Research Unit, Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, United Kingdom
| | - Steve Jeffery
- Lymphovascular Research Unit, Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, United Kingdom
| | - Kristiana Gordon
- Dermatology and Lymphovascular Medicine, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
| | - Pia Ostergaard
- Lymphovascular Research Unit, Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, United Kingdom
| | - Peter Mortimer
- Lymphovascular Research Unit, Molecular and Clinical Sciences Research Institute, St George’s, University of London, London, United Kingdom
- Dermatology and Lymphovascular Medicine, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
| | - Derek C. Macallan
- Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom
- Infection and Immunity Clinical Academic Group, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
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25
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Kim D, Tian W, Wu TTH, Xiang M, Vinh R, Chang JL, Gu S, Lee S, Zhu Y, Guan T, Schneider EC, Bao E, Dixon JB, Kao P, Pan J, Rockson SG, Jiang X, Nicolls MR. Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation. Circulation 2023; 148:1231-1249. [PMID: 37609838 PMCID: PMC10592179 DOI: 10.1161/circulationaha.123.064181] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 07/31/2023] [Indexed: 08/24/2023]
Abstract
BACKGROUND Lymphedema is a global health problem with no effective drug treatment. Enhanced T-cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T-cell activation. Characterizing this biology is relevant for developing much needed therapies. METHODS Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1-deficient (S1pr1LECKO) mice were generated. Disease progression was quantified by tail-volumetric and -histopathologic measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then cocultured with CD4 T cells, followed by an analysis of CD4 T-cell activation and pathway signaling. Last, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T-cell activation. RESULTS Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1P receptor 1 (S1PR1). LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T-cell infiltration in mouse lymphedema. LECs, isolated from S1pr1LECKO mice and cocultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs promoted T-helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. Human dermal LECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro, P-selectin blockade reduced the activation and differentiation of Th cells cocultured with shS1PR1-treated human dermal LECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSIONS This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T-cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition.
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Affiliation(s)
- Dongeon Kim
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Wen Tian
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Timothy Ting-Hsuan Wu
- Stanford University School of Medicine, Stanford, California, USA
- Department of Biochemistry, Stanford Bio-X, Stanford, California, USA
| | - Menglan Xiang
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Ryan Vinh
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Jason Lon Chang
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Shenbiao Gu
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Seunghee Lee
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Yu Zhu
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Torrey Guan
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Emilie Claire Schneider
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Evan Bao
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | | | - Peter Kao
- Stanford University School of Medicine, Stanford, California, USA
| | - Junliang Pan
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | | | - Xinguo Jiang
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Mark Robert Nicolls
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
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26
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Mishima T, Hosono K, Tanabe M, Ito Y, Majima M, Narumiya S, Miyaji K, Amano H. Thromboxane prostanoid signaling in macrophages attenuates lymphedema and facilitates lymphangiogenesis in mice : TP signaling and lymphangiogenesis. Mol Biol Rep 2023; 50:7981-7993. [PMID: 37540456 PMCID: PMC10520203 DOI: 10.1007/s11033-023-08620-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/21/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND Accumulating evidence suggests that prostaglandin E2, an arachidonic acid (AA) metabolite, enhances lymphangiogenesis in response to inflammation. However, thromboxane A2 (TXA2), another AA metabolite, is not well known. Thus, this study aimed to determine the role of thromboxane prostanoid (TP) signaling in lymphangiogenesis in secondary lymphedema. METHODS AND RESULTS Lymphedema was induced by the ablation of lymphatic vessels in mouse tails. Compared with wild-type mice, tail lymphedema in Tp-deficient mice was enhanced, which was associated with suppressed lymphangiogenesis as indicated by decreased lymphatic vessel area and pro-lymphangiogenesis-stimulating factors. Numerous macrophages were found in the tail tissues of Tp-deficient mice. Furthermore, the deletion of TP in macrophages increased tail edema and decreased lymphangiogenesis and pro-lymphangiogenic cytokines, which was accompanied by increased numbers of macrophages and gene expression related to a pro-inflammatory macrophage phenotype in tail tissues. In vivo microscopic studies revealed fluorescent dye leakage in the lymphatic vessels in the wounded tissues. CONCLUSIONS The results suggest that TP signaling in macrophages promotes lymphangiogenesis and prevents tail lymphedema. TP signaling may be a therapeutic target for improving lymphedema-related symptoms by enhancing lymphangiogenesis.
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Affiliation(s)
- Toshiaki Mishima
- Department of Cardiovascular Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kanako Hosono
- Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
| | - Mina Tanabe
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yoshiya Ito
- Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan.
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan.
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
| | - Masataka Majima
- Department of Medical Therapeutics, Kanagawa Institute of Technology, Atsugi, Kanagawa, 243-0292, Japan
| | - Shuh Narumiya
- Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Kagami Miyaji
- Department of Cardiovascular Surgery, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hideki Amano
- Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, 252-0374, Japan
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27
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Zhou Z, Sui X, Cao Z, Li X, Qing L, Tang J. Substance P promote macrophage M2 polarization to attenuate secondary lymphedema by regulating NF-kB/NLRP3 signaling pathway. Peptides 2023; 168:171045. [PMID: 37507091 DOI: 10.1016/j.peptides.2023.171045] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/25/2023] [Accepted: 06/09/2023] [Indexed: 07/30/2023]
Abstract
Secondary lymphedema often occurs after filariasis, trauma, lymph node dissection and radiation therapy, which is manifested by infiltration of inflammatory cells and fibrosis formation in pathologically. Substance P is a widely used neuropeptide in the field of tissue repair, while the regenerative potential of the substance P has not been proven in the secondary lymphedema. In this study, animal model of secondary lymphedema was constructed by excising the skin and subcutaneous lymphatic network in the tail of mice, and the degree of swelling in the tail of mice was evaluated after 6 weeks under the treatment with substance P. Immunofluorescence staining was also performed to assess immune cell infiltration, subcutaneous fibrosis and lymphangiogenesis. The results revealed that substance P significantly alleviated post-surgical lymphedema in mice. Furthermore, we found that substance P promoted macrophages M2 polarization, a process associated with downregulation of the NF-kB/NLRP3 pathway. After application of disodium clodronate (macrophage scavenger, CLO), the positive effect of substance P in lymphedema is significantly inhibited. In vitro experiments, we further demonstrated the polarizing effect of substance P on bone marrow-derived macrophages (BMDMs), while substance P inhibited the activation of the NF-kB/NLRP3 pathway in BMDMs after the treatment of lipopolysaccharide (LPS). In addition, polarized macrophages were demonstrated to promote the proliferation, tube-forming and migratory functions of human lymphatic endothelial cells (hLEC). In conclusion, our study provides preliminary evidence that substance P alleviates secondary lymphedema by promoting macrophage M2 polarization, and this therapeutic effect may be associated with downregulation of the NF-kB/NLRP3 pathway.
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Affiliation(s)
- Zekun Zhou
- Xiangya hospital of central south university, Changsha, China
| | - Xinlei Sui
- Xiangya hospital of central south university, Changsha, China
| | - Zheming Cao
- Xiangya hospital of central south university, Changsha, China
| | - Xiaoxiao Li
- Changsha Medical University, Changsha, China
| | - Liming Qing
- Xiangya hospital of central south university, Changsha, China.
| | - Juyu Tang
- Xiangya hospital of central south university, Changsha, China.
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Imai H, Kawase T, Yoshida S, Mese T, Roh S, Fujita A, Uchiki T, Sasaki A, Nagamatsu S, Takazawa A, Ichinohe T, Koshima I. Peripheral T cell profiling reveals downregulated exhaustion marker and increased diversity in lymphedema post-lymphatic venous anastomosis. iScience 2023; 26:106822. [PMID: 37250774 PMCID: PMC10212982 DOI: 10.1016/j.isci.2023.106822] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/17/2023] [Accepted: 05/02/2023] [Indexed: 05/31/2023] Open
Abstract
Lymphedema is a progressive condition accompanying cellulitis and angiosarcoma, suggesting its association with immune dysfunction. Lymphatic venous anastomosis (LVA) can provide relief from cellulitis and angiosarcoma. However, the immune status of peripheral T cells during lymphedema and post-LVA remains poorly understood. Using peripheral blood T cells from lymphedema, post-LVA, and healthy controls (HCs), we compared the profile of T cell subsets and T cell receptor (TCR) diversity. PD-1+ Tim-3 + expression was downregulated in post-LVA compared with lymphedema. IFN-γ levels in CD4+PD-1+ T cells and IL-17A levels in CD4+ T cells were downregulated in post-LVA compared with lymphedema. TCR diversity was decreased in lymphedema compared with HCs; such TCR skewing was drastically improved in post-LVA. T cells in lymphedema were associated with exhaustion, inflammation, and diminished diversity, which were relieved post-LVA. The results provide insights into the peripheral T cell population in lymphedema and highlight the immune modulatory importance of LVA.
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Affiliation(s)
- Hirofumi Imai
- International Center for Lymphedema, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Takakazu Kawase
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
- International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Aichi 470-1192, Japan
| | - Shuhei Yoshida
- International Center for Lymphedema, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Toshiro Mese
- International Center for Lymphedema, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Solji Roh
- International Center for Lymphedema, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Asuka Fujita
- Department of Plastic and Reconstructive Surgery, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Toshio Uchiki
- Department of Plastic and Reconstructive Surgery, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Ayano Sasaki
- Department of Plastic and Reconstructive Surgery, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Shogo Nagamatsu
- Department of Plastic and Reconstructive Surgery, Hiroshima University Hospital, Hiroshima 734-8551, Japan
| | - Atsushi Takazawa
- Department of Orthopaedic Surgery, Hiroshima Hiramatsu Hospital, Hiroshima 732-0816, Japan
| | - Tatsuo Ichinohe
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
| | - Isao Koshima
- International Center for Lymphedema, Hiroshima University Hospital, Hiroshima 734-8551, Japan
- Department of Plastic and Reconstructive Surgery, Hiroshima University Hospital, Hiroshima 734-8551, Japan
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Kim D, Tian W, Wu TTH, Xiang M, Vinh R, Chang J, Gu S, Lee S, Zhu Y, Guan T, Schneider EC, Bao E, Dixon JB, Kao P, Pan J, Rockson SG, Jiang X, Nicolls MR. Abnormal lymphatic S1P signaling aggravates lymphatic dysfunction and tissue inflammation. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.06.08.23291175. [PMID: 37398237 PMCID: PMC10312855 DOI: 10.1101/2023.06.08.23291175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
BACKGROUND Lymphedema is a global health problem with no effective drug treatment. Enhanced T cell immunity and abnormal lymphatic endothelial cell (LEC) signaling are promising therapeutic targets for this condition. Sphingosine-1-phosphate (S1P) mediates a key signaling pathway required for normal LEC function, and altered S1P signaling in LECs could lead to lymphatic disease and pathogenic T cell activation. Characterizing this biology is relevant for developing much-needed therapies. METHODS Human and mouse lymphedema was studied. Lymphedema was induced in mice by surgically ligating the tail lymphatics. Lymphedematous dermal tissue was assessed for S1P signaling. To verify the role of altered S1P signaling effects in lymphatic cells, LEC-specific S1pr1 -deficient ( S1pr1 LECKO ) mice were generated. Disease progression was quantified by tail-volumetric and -histopathological measurements over time. LECs from mice and humans, with S1P signaling inhibition, were then co-cultured with CD4 T cells, followed by an analysis of CD4 T cell activation and pathway signaling. Finally, animals were treated with a monoclonal antibody specific to P-selectin to assess its efficacy in reducing lymphedema and T cell activation. RESULTS Human and experimental lymphedema tissues exhibited decreased LEC S1P signaling through S1PR1. LEC S1pr1 loss-of-function exacerbated lymphatic vascular insufficiency, tail swelling, and increased CD4 T cell infiltration in mouse lymphedema. LECs, isolated from S1pr1 LECKO mice and co-cultured with CD4 T cells, resulted in augmented lymphocyte differentiation. Inhibiting S1PR1 signaling in human dermal LECs (HDLECs) promoted T helper type 1 and 2 (Th1 and Th2) cell differentiation through direct cell contact with lymphocytes. HDLECs with dampened S1P signaling exhibited enhanced P-selectin, an important cell adhesion molecule expressed on activated vascular cells. In vitro , P-selectin blockade reduced the activation and differentiation of Th cells co-cultured with sh S1PR1 -treated HDLECs. P-selectin-directed antibody treatment improved tail swelling and reduced Th1/Th2 immune responses in mouse lymphedema. CONCLUSION This study suggests that reduction of the LEC S1P signaling aggravates lymphedema by enhancing LEC adhesion and amplifying pathogenic CD4 T cell responses. P-selectin inhibitors are suggested as a possible treatment for this pervasive condition. Clinical Perspective What is New?: Lymphatic-specific S1pr1 deletion exacerbates lymphatic vessel malfunction and Th1/Th2 immune responses during lymphedema pathogenesis. S1pr1 -deficient LECs directly induce Th1/Th2 cell differentiation and decrease anti-inflammatory Treg populations. Peripheral dermal LECs affect CD4 T cell immune responses through direct cell contact.LEC P-selectin, regulated by S1PR1 signaling, affects CD4 T cell activation and differentiation.P-selectin blockade improves lymphedema tail swelling and decreases Th1/Th2 population in the diseased skin.What Are the Clinical Implications?: S1P/S1PR1 signaling in LECs regulates inflammation in lymphedema tissue.S1PR1 expression levels on LECs may be a useful biomarker for assessing predisposition to lymphatic disease, such as at-risk women undergoing mastectomyP-selectin Inhibitors may be effective for certain forms of lymphedema.
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Affiliation(s)
- Dongeon Kim
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Wen Tian
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Timothy Ting-Hsuan Wu
- Stanford University School of Medicine, Stanford, California, USA
- Department of Biochemistry, Stanford Bio-X, Stanford, California, USA
| | - Menglan Xiang
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Ryan Vinh
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Jason Chang
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Shenbiao Gu
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Seunghee Lee
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Yu Zhu
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Torrey Guan
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Emilie Claire Schneider
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Evan Bao
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | | | - Peter Kao
- Stanford University School of Medicine, Stanford, California, USA
| | - Junliang Pan
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | | | - Xinguo Jiang
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - Mark Robert Nicolls
- VA Palo Alto Health Care System, Palo Alto, California, USA
- Stanford University School of Medicine, Stanford, California, USA
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Maisel K, McClain CA, Bogseth A, Thomas SN. Nanotechnologies for Physiology-Informed Drug Delivery to the Lymphatic System. Annu Rev Biomed Eng 2023; 25:233-256. [PMID: 37000965 PMCID: PMC10879987 DOI: 10.1146/annurev-bioeng-092222-034906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2023]
Abstract
Accompanying the increasing translational impact of immunotherapeutic strategies to treat and prevent disease has been a broadening interest across both bioscience and bioengineering in the lymphatic system. Herein, the lymphatic system physiology, ranging from its tissue structures to immune functions and effects, is described. Design principles and engineering approaches to analyze and manipulate this tissue system in nanoparticle-based drug delivery applications are also elaborated.
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Affiliation(s)
- Katharina Maisel
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA;
| | - Claire A McClain
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA;
| | - Amanda Bogseth
- Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA;
| | - Susan N Thomas
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA;
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
- Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University, Atlanta, Georgia, USA
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Komagata S. Kanpumasatsu: A superficial self-massage with a dry towel to enhance relaxation and immune functions. JOURNAL OF INTERPROFESSIONAL EDUCATION & PRACTICE 2023; 31:100609. [PMID: 36776417 PMCID: PMC9905003 DOI: 10.1016/j.xjep.2023.100609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/22/2023] [Accepted: 02/03/2023] [Indexed: 04/16/2023]
Abstract
Prior to 2020, healthcare professionals in the United States already had high rate of burnout. Since 2020, the COVID-19 pandemic created an urgent need for public health measures to effectively mitigate its negative health impacts. Despite these measures including vaccination, masking, handwashing, and physical distancing, people continue to be affected by post-COVID conditions (PCC) or newly acquired infections. Promoting one's well-being and self-care, especially the methods that promote one's relaxation and immune functions will serve as valuable tools among all healthcare practitioners and educators. For example, Kanpumasatsu, a skin rubdown using a dry towel, is simple to instruct, safe, and a cost-containing self-care approach that has the potential to promote relaxation and improve one's immune functions. At the present moment, the evidence is limited and the mechanism of how kanpumasatsu improves immune functions has not been clearly documented. However, this author postulates this superficial massage causes the skin to stretch and enhances the lymphatic flow beneath the skin in a mechanism similar to that of lymphatic drainage massage. While the limited evidence of the health benefits of kanpumasatsu is available today, there is a potential for creating and enhancing instructional resources, conducting research and practice through awareness of kanpumasatsu among interprofessional educators and practitioners as a pilot self-care program to prevent burnout.
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Affiliation(s)
- Sachiko Komagata
- Dept. of Integrative Health & Exercise Science, Hackensack-Meridian Health School of Nursing and Wellness, Georgian Court University, Lakewood, NJ, USA
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Barthelemy J, Bogard G, Wolowczuk I. Beyond energy balance regulation: The underestimated role of adipose tissues in host defense against pathogens. Front Immunol 2023; 14:1083191. [PMID: 36936928 PMCID: PMC10019896 DOI: 10.3389/fimmu.2023.1083191] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 01/09/2023] [Indexed: 03/06/2023] Open
Abstract
Although the adipose tissue (AT) is a central metabolic organ in the regulation of whole-body energy homeostasis, it is also an important endocrine and immunological organ. As an endocrine organ, AT secretes a variety of bioactive peptides known as adipokines - some of which have inflammatory and immunoregulatory properties. As an immunological organ, AT contains a broad spectrum of innate and adaptive immune cells that have mostly been studied in the context of obesity. However, overwhelming evidence supports the notion that AT is a genuine immunological effector site, which contains all cell subsets required to induce and generate specific and effective immune responses against pathogens. Indeed, AT was reported to be an immune reservoir in the host's response to infection, and a site of parasitic, bacterial and viral infections. In addition, besides AT's immune cells, preadipocytes and adipocytes were shown to express innate immune receptors, and adipocytes were reported as antigen-presenting cells to regulate T-cell-mediated adaptive immunity. Here we review the current knowledge on the role of AT and AT's immune system in host defense against pathogens. First, we will summarize the main characteristics of AT: type, distribution, function, and extraordinary plasticity. Second, we will describe the intimate contact AT has with lymph nodes and vessels, and AT immune cell composition. Finally, we will present a comprehensive and up-to-date overview of the current research on the contribution of AT to host defense against pathogens, including the respiratory viruses influenza and SARS-CoV-2.
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Affiliation(s)
| | | | - Isabelle Wolowczuk
- Univ. Lille, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), Centre Hospitalier Universitaire de Lille (CHU Lille), Institut Pasteur de Lille, U1019 - UMR 9017 - Center for Infection and Immunity of Lille (CIIL), Lille, France
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Miyazaki T, Taketomi Y, Higashi T, Ohtaki H, Takaki T, Ohnishi K, Hosonuma M, Kono N, Akasu R, Haraguchi S, Kim-Kaneyama JR, Otsu K, Arai H, Murakami M, Miyazaki A. Hypercholesterolemic Dysregulation of Calpain in Lymphatic Endothelial Cells Interferes With Regulatory T-Cell Stability and Trafficking. Arterioscler Thromb Vasc Biol 2023; 43:e66-e82. [PMID: 36519468 DOI: 10.1161/atvbaha.122.317781] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 11/29/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND Although hypercholesterolemia reportedly counteracts lymphocyte trafficking across lymphatic vessels, the roles of lymphatic endothelial cells (LECs) in the lymphocyte regulations remain unclear. Previous studies showed that calpain-an intracellular modulatory protease-interferes with leukocyte dynamics in the blood microcirculation and is associated with hypercholesterolemic dysfunction in vascular endothelial cells. METHODS This study investigated whether the calpain systems in LECs associate with the LEC-lymphocyte interaction under hypercholesterolemia using gene-targeted mice. RESULTS Lipidomic analysis in hypercholesterolemic mice showed that several lysophospholipids, including lysophosphatidic acid, accumulated in the lymphatic environment. Lysophosphatidic acid enables the potentiation of calpain systems in cultured LECs, which limits their ability to stabilize regulatory T cells (Treg) without altering Th1/Th2 (T helper type1/2) subsets. This occurs via the proteolytic degradation of MEKK1 (mitogen-activated protein kinase kinase kinase 1) and the subsequent inhibition of TGF (transforming growth factor)-β1 production in LECs. Targeting calpain systems in LECs expanded Tregs in the blood circulation and reduced aortic atherosclerosis in hypercholesterolemic mice, concomitant with the reduction of proinflammatory macrophages in the lesions. Treg expansion in the blood circulation and atheroprotection in calpain-targeted mice was prevented by the administration of TGF-β type-I receptor inhibitor. Moreover, lysophosphatidic acid-induced calpain overactivation potentiated the IL (interleukin)-18/NF-κB (nuclear factor κB)/VCAM1 (vascular cell adhesion molecule 1) axis in LECs, thereby inhibiting lymphocyte mobility on the cells. Indeed, VCAM1 in LECs was upregulated in hypercholesterolemic mice and human cases of coronary artery disease. Neutralization of VCAM1 or targeting LEC calpain systems recovered afferent Treg transportation via lymphatic vessels in mice. CONCLUSIONS Calpain systems in LECs have a key role in controlling Treg stability and trafficking under hypercholesterolemia.
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Affiliation(s)
- Takuro Miyazaki
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
| | - Yoshitaka Taketomi
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine (Y.T., T.H., M.M.), the University of Tokyo, Japan
| | - Takayoshi Higashi
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine (Y.T., T.H., M.M.), the University of Tokyo, Japan
| | - Hirokazu Ohtaki
- Department of Anatomy (H.O.), Showa University School of Medicine, Tokyo, Japan
| | - Takashi Takaki
- Division of Electron Microscopy (T.T.), Showa University School of Medicine, Tokyo, Japan
| | - Koji Ohnishi
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan (K. Ohnishi)
| | - Masahiro Hosonuma
- Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan (M.H.)
| | - Nozomu Kono
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Graduate School of Medicine (N.K., H.A.), the University of Tokyo, Japan
| | - Risako Akasu
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
| | - Shogo Haraguchi
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
| | - Joo-Ri Kim-Kaneyama
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
| | - Kinya Otsu
- The School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom (K. Otsu)
| | - Hiroyuki Arai
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Graduate School of Medicine (N.K., H.A.), the University of Tokyo, Japan
| | - Makoto Murakami
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine (Y.T., T.H., M.M.), the University of Tokyo, Japan
| | - Akira Miyazaki
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
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Burton JS, Sletten AC, Marsh E, Wood MD, Sacks JM. Adipose Tissue in Lymphedema: A Central Feature of Pathology and Target for Pharmacologic Therapy. Lymphat Res Biol 2023; 21:2-7. [PMID: 35594294 DOI: 10.1089/lrb.2022.0003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Lymphedema is a chronic condition of impaired lymphatic flow that results in limb swelling and debilitation. The pathophysiology of lymphedema is characterized by lymphatic stasis that triggers inflammation, fibrosis, and adipose tissue deposition in the extremities. Most often, this condition occurs in cancer survivors in the years after treatment with combinations of surgery, radiation, or chemotherapy, with the major risk factor being lymph node dissection. Interestingly, obesity and body mass index are independent risk factors for development of lymphedema, suggesting interactions between adipose and lymphatic tissue biology. Currently, treatment of lymphedema involves palliative approaches, including compression garments and physical therapy, and surgical approaches, including liposuction, lymphovenous bypass, and vascularized lymph node transfer. Emerging lymphedema therapies that focus on weight loss or reducing inflammation have been tested in recent clinical trials, yielding mixed results with no effect on limb volumes or changes in bioimpedance measurements. These studies highlight the need for novel therapeutic strategies that target the driving forces of lymphedema. In this light, animal models of lymphedema demonstrate a role of adipose tissue in the progression of lymphedema and suggest these processes may be targeted in the treatment of lymphedema. Herein, we review both conventional and experimental therapies for lymphedema as well as the defining characteristics of its pathophysiology. We place emphasis on the aberrant fibroadipose tissue accumulation in lymphedema and propose a new approach to experimental treatment at the level of adipocyte metabolism.
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Affiliation(s)
- Jackson S Burton
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Arthur C Sletten
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Evan Marsh
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Matthew D Wood
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Justin M Sacks
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
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Brown S, Dayan JH, Kataru RP, Mehrara BJ. The Vicious Circle of Stasis, Inflammation, and Fibrosis in Lymphedema. Plast Reconstr Surg 2023; 151:330e-341e. [PMID: 36696336 PMCID: PMC9881755 DOI: 10.1097/prs.0000000000009866] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
SUMMARY Lymphedema is a progressive disease of the lymphatic system arising from impaired lymphatic drainage, accumulation of interstitial fluid, and fibroadipose deposition. Secondary lymphedema resulting from cancer treatment is the most common form of the disease in developed countries, affecting 15% to 40% of patients with breast cancer after lymph node dissection. Despite recent advances in microsurgery, outcomes remain variable and, in some cases, inadequate. Thus, development of novel treatment strategies is an important goal. Research over the past decade suggests that lymphatic injury initiates a chronic inflammatory response that regulates the pathophysiology of lymphedema. T-cell inflammation plays a key role in this response. In this review, the authors highlight the cellular and molecular mechanisms of lymphedema and discuss promising preclinical therapies.
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Affiliation(s)
- Stav Brown
- From the Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
| | - Joseph H Dayan
- From the Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
| | - Raghu P Kataru
- From the Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
| | - Babak J Mehrara
- From the Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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Obesity-associated mesenteric lymph leakage impairs the trafficking of lipids, lipophilic drugs and antigens from the intestine to mesenteric lymph nodes. Eur J Pharm Biopharm 2022; 180:319-331. [DOI: 10.1016/j.ejpb.2022.10.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 10/06/2022] [Accepted: 10/19/2022] [Indexed: 11/23/2022]
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Lee S, Lee DG, Kim KT. Temporal Changes in Subcutaneous Fibrosis in Patients with Lower Extremity Lymphedema Following Surgery for Gynecologic Cancer: A Computed Tomography-Based Quantitative Analysis. Diagnostics (Basel) 2022; 12:diagnostics12081949. [PMID: 36010297 PMCID: PMC9406798 DOI: 10.3390/diagnostics12081949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/11/2022] [Accepted: 08/11/2022] [Indexed: 11/16/2022] Open
Abstract
Lymphedema causes inflammation, which provokes fibrosis within the epifascial tissue. Temporal change in fibrosis according to severity of the lymphedema has not been widely investigated. We aimed to study the quantitative changes in epifascial fibrosis during lymphedema treatment using computed tomography (CT). Forty-five patients (mean age: 57.75 ± 11.12 years) who developed lymphedema following gynecologic surgery were included in this retrospective study. Two weeks of complete decongestive therapy and continued self-bandaging or compression garments were prescribed under regular follow-up monitoring. Lower-extremity epifascial fibrosis was quantitatively analyzed on the initial and follow-up CT scans. Circumference, skin fibrosis, subcutaneous tissue, and fibrosis ratio were calculated in the axial scan. Based on the change in lymphedema severity, we divided subjects into ‘improved’ and ‘aggravated’ groups. The affected lower extremities showed higher circumference, more skin fibrosis and subcutaneous tissue, and higher fibrosis ratio than the unaffected sides on initial CT scan. At follow-up, compared to the aggravated group, the improved group showed significant decreases in fibrosis of skin and subcutaneous tissue and fibrosis ratio. Subcutaneous fibrosis was reversible with volume resolution of lymphedema. Therapeutic approaches should be established on the basis of the reversible nature of fibrotic changes in patients with lower extremity lymphedema.
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Affiliation(s)
- Soyoung Lee
- Department of Rehabilitation Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu 42601, Korea
| | - Dong Gyu Lee
- Department of Physical Medicine and Rehabilitation, Yeungnam University College of Medicine, Daegu 42415, Korea
| | - Kyoung Tae Kim
- Department of Rehabilitation Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu 42601, Korea
- Correspondence: ; Tel.: +82-53-258-7692
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Ogino R, Yokooji T, Hayashida M, Suda S, Yamakawa S, Hayashida K. Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema. Int J Mol Sci 2022; 23:ijms23147614. [PMID: 35886961 PMCID: PMC9322118 DOI: 10.3390/ijms23147614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 02/04/2023] Open
Abstract
Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.
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Affiliation(s)
- Ryohei Ogino
- Department of Frontier Science for Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (R.O.); (T.Y.)
| | - Tomoharu Yokooji
- Department of Frontier Science for Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (R.O.); (T.Y.)
| | - Maiko Hayashida
- Department of Psychiatry, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan;
| | - Shota Suda
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
| | - Sho Yamakawa
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
| | - Kenji Hayashida
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
- Correspondence: ; Tel.: +81-853-20-2210
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Sung C, Wang S, Hsu J, Yu R, Wong AK. Current Understanding of Pathological Mechanisms of Lymphedema. Adv Wound Care (New Rochelle) 2022; 11:361-373. [PMID: 34521256 PMCID: PMC9051876 DOI: 10.1089/wound.2021.0041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Significance: Lymphedema is a common disease that affects hundreds of millions of people worldwide with significant financial and social burdens. Despite increasing prevalence and associated morbidities, the mainstay treatment of lymphedema is largely palliative without an effective cure due to incomplete understanding of the disease. Recent Advances: Recent studies have described key histological and pathological processes that contribute to the progression of lymphedema, including lymphatic stasis, inflammation, adipose tissue deposition, and fibrosis. This review aims to highlight cellular and molecular mechanisms involved in each of these pathological processes. Critical Issues: Despite recent advances in the understanding of the pathophysiology of lymphedema, cellular and molecular mechanisms underlying the disease remains elusive due to its complex nature. Future Directions: Additional research is needed to gain a better insight into the cellular and molecular mechanisms underlying the pathophysiology of lymphedema, which will guide the development of therapeutic strategies that target specific pathology of the disease.
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Affiliation(s)
- Cynthia Sung
- Keck School of Medicine of USC, Los Angeles, California, USA.,Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA
| | - Sarah Wang
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Jerry Hsu
- Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.,Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Roy Yu
- Keck School of Medicine of USC, Los Angeles, California, USA
| | - Alex K. Wong
- Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.,Correspondence: Division of Plastic Surgery, City of Hope National Medical Center, 1500 Duarte Road, Familian Science Building 1018, Duarte, CA 91010, USA.
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Kataru RP, Park HJ, Shin J, Baik JE, Sarker A, Brown S, Mehrara BJ. Structural and Functional Changes in Aged Skin Lymphatic Vessels. FRONTIERS IN AGING 2022; 3:864860. [PMID: 35821848 PMCID: PMC9261401 DOI: 10.3389/fragi.2022.864860] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/11/2022] [Indexed: 11/13/2022]
Abstract
Lymphatic structure and function play a critical role in fluid transport, antigen delivery, and immune homeostasis. A dysfunctional lymphatic system is associated with chronic low-grade inflammation of peripheral tissues, poor immune responses, and recurrent infections, which are also hallmarks of aging pathology. Previous studies have shown that aging impairs lymphatic structure and function in a variety of organ systems, including the intestines and central nervous system. However, previous studies are mostly limited to qualitative analysis of lymphatic structural changes and quantification of intestinal collecting vessel contractile function. It is not clear whether decreased lymphatic function contributes to pathological conditions related to aging, nor how it affects the skin immune microenvironment. Further, the effects of aging on skin initial and collecting lymphatic vessels, dendritic cell (DC) migration, cutaneous lymphatic pumping, and VEGFR-3 signaling in lymphatic endothelial cells (LECs) have not been quantitatively analyzed. Here, using fluorescent immunohistochemistry and flow cytometry, we confirm that aging decreases skin initial and collecting lymphatic vessel density. Indocyanine green (ICG) lymphangiography and DC migration assays confirm that aging decreases both fluid pumping and cell migration via lymphatic vessels. At the cellular level, aging causes decreased VEGFR-3 signaling, leading to increased LEC apoptosis and senescence. Finally, we determined that aging causes decreased lymphatic production of chemokines and alters LEC expression of junctional and adhesion molecules. This in turn leads to increased peri-lymphatic inflammation and nitrosative stress that might contribute to aging pathology in a feed-forward manner. Taken together, our study, in addition to quantitatively corroborating previous findings, suggests diverse mechanisms that contribute to lymphatic dysfunction in aging that in turn exacerbate the pathology of aging in a feed-forward manner.
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Affiliation(s)
- Raghu P. Kataru
- The Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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41
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Dong D, Wang H, Chen L, Wang W, Liu T. Hormone Therapy: A Potential Risk Factor Affecting Survival and Functional Restoration of Transplanted Lymph Nodes. Front Pharmacol 2022; 13:853859. [PMID: 35431925 PMCID: PMC9008310 DOI: 10.3389/fphar.2022.853859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 03/09/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Transplantation of lymph nodes (LNs) is an increasingly popular option for treating lymphedema. Increasing evidence indicates an intrinsic correlation between estrogen signaling and the lymphatic system. We explored the effects of 17β estradiol and antiestrogen treatment (tamoxifen) on the survival and functional restoration of transplanted popliteal lymph nodes (PLNs). Methods: A total of forty-eight ovariectomized mice were divided into three groups of 16: OVX + E2 (treated with 17β-estradiol), OVX + TMX (treated with tamoxifen), and OVX (control; treated with olive oil as a solvent). After 2 weeks, PLNs were transplanted. Then, reconnections of lymphatic vessels were observed, and the morphology and survival of transplanted PLNs were evaluated 4 weeks after transplantation. T cells, B cells, lymphatic vessels, and high endothelial venules (HEVs) were subjected to immunofluorescence staining or immunohistochemical staining and quantified. Results: The percentage of lymphatic reconnections was 93.75% in the OVX + E2 group, 68.75% in the OVX + TMX group, and 75% in the OVX group. Surviving PLNs were observed in 16 of 16 in the OVX + E2 group, seven of 16 in the OVX + TMX group, and 13 of 16 in the OVX group. The mean size of PLNs in the largest cross section of the OVX + TMX group was significantly lower than that in the other groups. The distributions of B cells and T cells in surviving PLNs were similar to those in normal LNs. The ratio of dilated HEVs/total HEVs and density of lymphatic vessels in the OVX + E2 group were the highest among the three groups, whereas the lowest ratio and density were observed in the OVX + TMX group. Conclusion: Tamoxifen treatment might lead to cellular loss of transplanted LNs and interfere with the structural reconstruction and functional restoration, thereby inhibiting the survival of transplanted PLNs. Estrogen treatment facilitated the maintenance and regeneration of functional HEVs as well as lymphangiogenesis.
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Affiliation(s)
- Dong Dong
- Department of Plastic and Aesthetic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China
- Shanghai Medical College of Fudan University, Shanghai, China
| | - Heng Wang
- Department of Plastic and Aesthetic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China
- Shanghai Medical College of Fudan University, Shanghai, China
| | - Liang Chen
- Department of Plastic and Aesthetic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Wei Wang
- Department of Plastic and Aesthetic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China
- Shanghai Medical College of Fudan University, Shanghai, China
| | - Tianyi Liu
- Department of Plastic and Aesthetic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, China
- *Correspondence: Tianyi Liu,
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42
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Kolarzyk AM, Wong G, Lee E. Lymphatic Tissue and Organ Engineering for In Vitro Modeling and In Vivo Regeneration. Cold Spring Harb Perspect Med 2022; 12:a041169. [PMID: 35288402 PMCID: PMC9435571 DOI: 10.1101/cshperspect.a041169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The lymphatic system has an important role in maintaining fluid homeostasis and transporting immune cells and biomolecules, such as dietary fat, metabolic products, and antigens in different organs and tissues. Therefore, impaired lymphatic vessel function and/or lymphatic vessel deficiency can lead to numerous human diseases. The discovery of lymphatic endothelial markers and prolymphangiogenic growth factors, along with a growing number of in vitro and in vivo models and technologies has expedited research in lymphatic tissue and organ engineering, advancing therapeutic strategies. In this article, we describe lymphatic tissue and organ engineering in two- and three-dimensional culture systems and recently developed microfluidics and organ-on-a-chip systems in vitro. Next, we discuss advances in lymphatic tissue and organ engineering in vivo, focusing on biomaterial and scaffold engineering and their applications for lymphatic vessels and lymphoid organ regeneration. Last, we provide expert perspective and prospects in the field of lymphatic tissue engineering.
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Affiliation(s)
- Anna M Kolarzyk
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Ithaca, New York 14853, USA
- Biomedical and Biological Sciences PhD Program, Ithaca, New York 14853, USA
| | - Gigi Wong
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Ithaca, New York 14853, USA
- Biological Sciences, Cornell University, Ithaca, New York 14853, USA
| | - Esak Lee
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Ithaca, New York 14853, USA
- Biomedical and Biological Sciences PhD Program, Ithaca, New York 14853, USA
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43
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Lafuente H, Jaunarena I, Ansuategui E, Lekuona A, Izeta A. Cell therapy as a treatment of secondary lymphedema: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:578. [PMID: 34801084 PMCID: PMC8605543 DOI: 10.1186/s13287-021-02632-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/16/2021] [Indexed: 12/09/2022] Open
Abstract
Background Lymphedema, the accumulation of interstitial fluid caused by poor lymphatic drainage, is a progressive and permanent disease with no curative treatment. Several studies have evaluated cell-based therapies in secondary lymphedema, but no meta-analysis has been performed to assess their efficacy. Methods We conducted a systematic review and meta-analysis of all available preclinical and clinical studies, with assessment of their quality and risk of bias. Results A total of 20 articles using diverse cell types were selected for analysis, including six clinical trials and 14 pre-clinical studies in three species. The meta-analysis showed a positive effect of cell-based therapies on relevant disease outcomes (quantification of edema, density of lymphatic capillaries, evaluation of the lymphatic flow, and tissue fibrosis). No significant publication bias was observed. Conclusion Cell-based therapies have the potential to improve secondary lymphedema. The underlying mechanisms remain unclear. Due to relevant heterogeneity between studies, further randomized controlled and blinded studies are required to substantiate the use of these novel therapies in clinical practice.
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Affiliation(s)
- Hector Lafuente
- Tissue Engineering Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain
| | - Ibon Jaunarena
- Gynecology Oncology Unit, Donostia University Hospital, 20014, San Sebastián, Spain.,Obstetrics and Gynaecology Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain
| | - Eukene Ansuategui
- Clinical Epidemiology Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain
| | - Arantza Lekuona
- Gynecology Oncology Unit, Donostia University Hospital, 20014, San Sebastián, Spain.,Obstetrics and Gynaecology Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain
| | - Ander Izeta
- Tissue Engineering Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain. .,School of Engineering, Tecnun-University of Navarra, 20009, San Sebastián, Spain.
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44
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Dai M, Minematsu T, Ogawa Y, Kawamoto A, Nakagami G, Sanada H. Association of Dermal Hypoechogenicity and Cellulitis History in Patients with Lower Extremity Lymphedema: A Cross-Sectional Observational Study. Lymphat Res Biol 2021; 20:376-381. [PMID: 34762544 DOI: 10.1089/lrb.2021.0004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background: Recurrent cellulitis has high impact on physical, psychological, and social aspects for lymphedema patients. We speculated that identification of characteristics of skin and subcutaneous adipose tissue with cellulitis history can help considering new approach for prevention of recurrent cellulitis in lymphedema patients. Therefore, in this study, we aimed to noninvasively identify the ultrasonographic features of skin and subcutaneous tissue of lymphedema in patients with a cellulitis history. Method and Results: This was a cross-sectional study, and all data were collected from patients' medical records. We assessed ultrasonographic images of the lower extremity of patients with lymphedema that were obtained in a lymphedema clinic. The ultrasonographic images were analyzed on the basis of the following five features: dermal hypoechogenicity, unclear dermal border, unclear superficial fascia, increased subcutaneous echogenicity, and subcutaneous cobblestone appearance. Fifty-two ultrasonographic images from 19 female patients with lower extremity lymphedema, including 8 with and 11 without a cellulitis history, were analyzed. The proportion of dermal hypoechogenicity on the upper leg was significantly higher in the patients with than in those without a cellulitis history (75.0% vs. 9.1%, p = 0.006). Conclusion: Cellulitis history in lymphedema patients appears to be associated with dermal hypoechogenicity, particularly in the proximal lower extremity. This finding suggests that it may be the initial step to consider new approach for prevention of recurrent cellulitis in lymphedema patients.
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Affiliation(s)
- Misako Dai
- Department of Skincare Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Research Center for Implementation Nursing Science Initiative, School of Health Sciences, Fujita Health University, Aich, Japan
| | - Takeo Minematsu
- Department of Skincare Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Division of Care Innovation, Global Nursing Research Center, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Atsuo Kawamoto
- Division of Ultrasound, Department of Diagnostic Imaging, Tokyo Medical University Hospital, Tokyo, Japan
| | - Gojiro Nakagami
- Division of Care Innovation, Global Nursing Research Center, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiromi Sanada
- Division of Care Innovation, Global Nursing Research Center, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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45
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Boyages J, Cave AE, Naidoo D, Ee CCL. Weight Gain and Lymphedema After Breast Cancer Treatment: Avoiding the Catch-22? Lymphat Res Biol 2021; 20:409-416. [PMID: 34748426 DOI: 10.1089/lrb.2020.0048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Background: Overweight and obesity are strongly implicated in breast cancer (BC) development and are also a risk factor for BC-related lymphedema (BCRL). Materials and Methods: An online cross-sectional survey was conducted between November 2017 and January 2018. Analyses were restricted to women with localized BC, who provided information about BCRL (n = 238). Most women were not experiencing BCRL (55.46%). Results: Mean self-reported weight at diagnosis was 68.55 kg for women without BCRL and 74.43 kg for women with BCRL (p = 0.0021). In this study, 50.9% with BCRL were overweight/obese at diagnosis (body mass index [BMI] ≥25) compared with 36.4% of women without BCRL (p = 0.003). For women without BCRL, 12.12% were classified as obese (BMI ≥30) versus 20.75% with BCRL. Women with BCRL were more likely to have gained >5% of body weight (p = 0.03), be currently overweight or obese (p = 0.004), and less active (48.11%) than they were at diagnosis than women without BCRL (33.33%) (p = 0.042). Having a structured exercise program, following a prescribed diet, and being accountable to someone else were identified as the main facilitators to successful weight loss and weight maintenance. Conclusions: Clinicians should consider obesity when personalizing axillary treatment and encourage lifestyle interventions and lymphedema screening after BC treatment.
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Affiliation(s)
- John Boyages
- ICON Cancer Centre, Sydney Adventist Hospital, Wahroonga, Australia.,Australian Lymphoedema Education Research and Treatment (ALERT), Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia
| | - Adele E Cave
- NICM Health Research Institute, Western Sydney University, Penrith, Australia
| | - Dhevaksha Naidoo
- NICM Health Research Institute, Western Sydney University, Penrith, Australia
| | - Carolyn C L Ee
- NICM Health Research Institute, Western Sydney University, Penrith, Australia
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46
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Fu X, He Y, Li M, Huang Z, Najafi M. Targeting of the tumor microenvironment by curcumin. Biofactors 2021; 47:914-932. [PMID: 34375483 DOI: 10.1002/biof.1776] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
The tumor microenvironment (TME) is made up of several cells and molecules that affect the survival of cancer cells. Indeed, certain (immunosuppressive) cells which promote tumors can promote the growth of tumors by stimulating the proliferation of cancer cells and promoting angiogenesis. During tumor growth, antitumoral immunity includes natural killer cells and CD8+ T cells cannot overcome immunosuppressive responses and cancer cell proliferation. In order to achieve the appropriate therapeutic response, we must kill cancer cells and suppress the release of immunosuppressive molecules. The balance between anti-tumor immunity and immunosuppressive cells, such as regulatory T cells (Tregs), cancer-associated fibroblasts, tumor-associated macrophages, and myeloid-derived suppressor cells plays a key role in the suppression or promotion of cancer cells. Curcumin is a plant-derived agent that has shown interesting properties for cancer therapy. It has shown that not only directly inhibit the growth of cancer cells, but can also modulate the growth and activity of immunosuppressant and tumor-promoting cells. In this review, we explain how curcumin modulates interactions within TME in favor of tumor treatment. The potential modulating effects of curcumin on the responses of cancer cells to treatment modalities such as immunotherapy will also be discussed.
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Affiliation(s)
- Xiao Fu
- College of Basic Medicine, Shaoyang University, Shaoyang, China
| | - Yingni He
- College of Basic Medicine, Shaoyang University, Shaoyang, China
| | - Mu Li
- College of Basic Medicine, Shaoyang University, Shaoyang, China
| | - Zezhi Huang
- Shaoyang Key Laboratory of Molecular Biology Diagnosis, Shaoyang, China
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
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47
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Yusof KM, Groen K, Rosli R, Avery-Kiejda KA. Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema. Front Cell Dev Biol 2021; 9:732415. [PMID: 34733847 PMCID: PMC8558478 DOI: 10.3389/fcell.2021.732415] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 10/01/2021] [Indexed: 01/07/2023] Open
Abstract
Secondary lymphedema is characterized by lymphatic fluid retention and subsequent tissue swelling in one or both limbs that can lead to decreased quality of life. It often arises after loss, obstruction, or blockage of lymphatic vessels due to multifactorial modalities, such as lymphatic insults after surgery, immune system dysfunction, deposition of fat that compresses the lymphatic capillaries, fibrosis, and inflammation. Although secondary lymphedema is often associated with breast cancer, the condition can occur in patients with any type of cancer that requires lymphadenectomy such as gynecological, genitourinary, or head and neck cancers. MicroRNAs demonstrate pivotal roles in regulating gene expression in biological processes such as lymphangiogenesis, angiogenesis, modulation of the immune system, and oxidative stress. MicroRNA profiling has led to the discovery of the molecular mechanisms involved in the pathophysiology of auto-immune, inflammation-related, and metabolic diseases. Although the role of microRNAs in regulating secondary lymphedema is yet to be elucidated, the crosstalk between microRNAs and molecular factors involved in the pathological features of lymphedema, such as skin fibrosis, inflammation, immune dysregulation, and aberrant lipid metabolism have been demonstrated in several studies. MicroRNAs have the potential to serve as biomarkers for diseases and elucidation of their roles in lymphedema can provide a better understanding or new insights of the mechanisms underlying this debilitating condition.
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Affiliation(s)
- Khairunnisa’ Md Yusof
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| | - Kira Groen
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
| | - Rozita Rosli
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
| | - Kelly A. Avery-Kiejda
- Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, The University of Newcastle, Newcastle, NSW, Australia
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48
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Jannaway M, Scallan JP. VE-Cadherin and Vesicles Differentially Regulate Lymphatic Vascular Permeability to Solutes of Various Sizes. Front Physiol 2021; 12:687563. [PMID: 34621180 PMCID: PMC8491776 DOI: 10.3389/fphys.2021.687563] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/24/2021] [Indexed: 01/04/2023] Open
Abstract
Lymphatic vascular permeability prevents lymph leakage that is associated with lymphedema, lymphatic malformations, obesity, and inflammation. However, the molecular control of lymphatic permeability remains poorly understood. Recent studies have suggested that adherens junctions and vesicle transport may be involved in regulating lymphatic vessel permeability. To determine the contribution of each transport pathway, we utilized an ex vivo permeability assay to directly measure the solute flux of various molecular weight solutes across a range of pressures in intact murine collecting lymphatic vessels. Pharmacological and biological tools were used to probe the relative contributions of vesicles and junction proteins in the lymphatic vasculature. We show that the permeability of collecting lymphatic vessels is inversely related to the solute molecular weight. Further, our data reveal that vesicles selectively transport BSA, as an inhibitor of vesicle formation significantly decreased the permeability to BSA (∼60% decrease, n = 8, P = 0.02), but not to 3 kDa dextran (n = 7, P = 0.41), α-lactalbumin (n = 5, P = 0.26) or 70 kDa dextran (n = 8, P = 0.13). In contrast, disruption of VE-cadherin binding with a function blocking antibody significantly increased lymphatic vessel permeability to both 3 kDa dextran (5.7-fold increase, n = 5, P < 0.0001) and BSA (5.8-fold increase, n = 5, P < 0.0001). Thus, in the lymphatic vasculature, adherens junctions did not exhibit selectivity for any of the solutes tested here, whereas vesicles specifically transport BSA. Overall, the findings suggest that disease states that disrupt VE-cadherin localization or expression will cause significant leakage of solutes and fluid from the lymphatic vasculature.
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Affiliation(s)
- Melanie Jannaway
- Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Joshua P Scallan
- Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
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49
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Henderson AR, Ilan IS, Lee E. A bioengineered lymphatic vessel model for studying lymphatic endothelial cell-cell junction and barrier function. Microcirculation 2021; 28:e12730. [PMID: 34569678 DOI: 10.1111/micc.12730] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 09/09/2021] [Accepted: 09/20/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Lymphatic vessels (LVs) maintain fluid homeostasis by draining interstitial fluid. A failure in lymphatic drainage triggers lymphatic diseases such as lymphedema. Since lymphatic drainage is regulated by lymphatic barrier function, developing experimental models that assess lymphatic barrier function is critical for better understanding of lymphatic physiology and disease. METHODS We built a lymphatic vessel-on-chip (LV-on-chip) by fabricating a microfluidic device that includes a hollow microchannel embedded in three-dimensional (3D) hydrogel. Employing luminal flow in the microchannel, human lymphatic endothelial cells (LECs) seeded in the microchannel formed an engineered LV exhibiting 3D conduit structure. RESULTS Lymphatic endothelial cells formed relatively permeable junctions in 3D collagen 1. However, adding fibronectin to the collagen 1 apparently tightened LEC junctions. We tested lymphatic barrier function by introducing dextran into LV lumens. While LECs in collagen 1 showed permeable barriers, LECs in fibronectin/collagen 1 showed reduced permeability, which was reversed by integrin α5 inhibition. Mechanistically, LECs expressed inactivated integrin α5 in collagen 1. However, integrin α5 is activated in fibronectin and enhances barrier function. Integrin α5 activation itself also tightened LEC junctions in the absence of fibronectin. CONCLUSIONS Lymphatic vessel-on-chip reveals integrin α5 as a regulator of lymphatic barrier function and provides a platform for studying lymphatic barrier function in various conditions.
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Affiliation(s)
- Aria R Henderson
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
| | - Isabelle S Ilan
- College of Human Ecology, Cornell University, Ithaca, New York, USA
| | - Esak Lee
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA
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50
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Kataru RP, Baik JE, Park HJ, Ly CL, Shin J, Schwartz N, Lu TT, Ortega S, Mehrara BJ. Lymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function. Sci Signal 2021; 14:eabc0836. [PMID: 34376570 PMCID: PMC8567054 DOI: 10.1126/scisignal.abc0836] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Exogenous administration of lymphangiogenic growth factors is widely used to study changes in lymphatic function in pathophysiology. However, this approach can result in off-target effects, thereby generating conflicting data. To circumvent this issue, we modulated intracellular VEGF-C signaling by conditionally knocking out the lipid phosphatase PTEN using the Vegfr3 promoter to drive the expression of Cre-lox in lymphatic endothelial cells (LECs). PTEN is an intracellular brake that inhibits the downstream effects of the activation of VEGFR3 by VEGF-C. Activation of Cre-lox recombination in adult mice resulted in an expanded functional lymphatic network due to LEC proliferation that was independent of lymphangiogenic growth factor production. Furthermore, compared with lymphangiogenesis induced by VEGF-C injection, LECPTEN animals had mature, nonleaky lymphatics with intact cell-cell junctions and reduced local tissue inflammation. Last, compared with wild-type or VEGF-C-injected mice, LECPTEN animals had an improved capacity to resolve inflammatory responses. Our findings indicate that intracellular modulation of lymphangiogenesis is effective in inducing functional lymphatic networks and has no off-target inflammatory effects.
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Affiliation(s)
- Raghu P Kataru
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
| | - Jung Eun Baik
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA
| | - Hyeung Ju Park
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA
| | - Catherine L Ly
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA
| | - Jinyeon Shin
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA
| | - Noa Schwartz
- Autoimmunity and Inflammation Program and Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA
| | - Theresa T Lu
- Autoimmunity and Inflammation Program and Rheumatology, Hospital for Special Surgery, New York, NY 10021, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Sagrario Ortega
- Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, 20829, Spain
| | - Babak J Mehrara
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA
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