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1
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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: 15] [Impact Index Per Article: 7.5] [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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2
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Bekkhus T, Olofsson A, Sun Y, Magnusson PU, Ulvmar MH. Stromal transdifferentiation drives lipomatosis and induces extensive vascular remodeling in the aging human lymph node. J Pathol 2023; 259:236-253. [PMID: 36367235 PMCID: PMC10108032 DOI: 10.1002/path.6030] [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] [Received: 07/25/2022] [Revised: 10/18/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022]
Abstract
Lymph node (LN) lipomatosis is a common but rarely discussed phenomenon associated with aging that involves a gradual exchange of the LN parenchyma into adipose tissue. The mechanisms behind these changes and the effects on the LN are unknown. We show that LN lipomatosis starts in the medullary regions of the human LN and link the initiation of lipomatosis to transdifferentiation of LN fibroblasts into adipocytes. The latter is associated with a downregulation of lymphotoxin beta expression. We also show that isolated medullary and CD34+ fibroblasts, in contrast to the reticular cells of the T-cell zone, display an inherently higher sensitivity for adipogenesis. Progression of lipomatosis leads to a gradual loss of the medullary lymphatic network, but at later stages, collecting-like lymphatic vessels are found inside the adipose tissue. The stromal dysregulation includes a dramatic remodeling and dilation of the high endothelial venules associated with reduced density of naïve T-cells. Abnormal clustering of plasma cells is also observed. Thus, LN lipomatosis causes widespread stromal dysfunction with consequences for the immune contexture of the human LN. Our data warrant an increased awareness of LN lipomatosis as a factor contributing to decreased immune functions in the elderly and in disease. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Tove Bekkhus
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Anna Olofsson
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Ying Sun
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Peetra U Magnusson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Maria H Ulvmar
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
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3
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Ernst AM, Bauer H, Bauer HC, Steiner M, Malfertheiner A, Lipp AT. Lipedema Research-Quo Vadis? J Pers Med 2022; 13:98. [PMID: 36675759 PMCID: PMC9860653 DOI: 10.3390/jpm13010098] [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: 12/06/2022] [Revised: 12/25/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
When studying the current literature, one might get the impression that lipedema is a "modern" disease, with increasing incidence and augmenting prevalence throughout Western countries during the last decade. However, a quick look into older textbooks shows that disproportionate accumulation of fat in female bodies has long been known without being recognized as an independent disease. Nevertheless, it was not until 1940 that Allen and Hines described a "syndrome characterized by fat legs and orthostatic edema" in a seminal publication. The mere awareness that people who have lipedema are not just overweight but suffer from a yet poorly defined pathological condition, may be considered a decisive leap forward in the understanding of lipedema. A number of comprehensive publications have since dealt with the clinical presentation of lipedema and have provided the first clues towards the potential pathological mechanisms underlying its initiation and progression. Nevertheless, despite all effort that has been undertaken to unravel lipedema pathology, many questions have remained unanswered. What can be deduced with certainty from all experimental and medical evidence available so far is that lipedema is neither a cosmetic problem nor is it a problem of lifestyle but should be accepted as a serious disease with yet undetermined genetic background, which makes women's lives unbearable from both a physical and psychological point of view. To date, results from clinical inspections have led to the categorization of various types and stages of lipedema, describing how the extremities are affected and evaluating its progression, as demonstrated by skin alterations, adipose tissue volume increase and physical and everyday-behavioral impediments. There is accumulating evidence showing that advanced stages of lipedema are usually accompanied by excessive weight or obesity. Thus, it is not unreasonable to assume that the progression of lipedema is largely driven by weight gain and the pathological alterations associated with it. Similarly, secondary lymphedema is frequently found in lipedema patients at advanced stages. Needless to say, both conditions considerably blur the clinical presentation of lipedema, making diagnosis difficult and scientific research challenging. The present literature review will focus on lipedema research, based on evidence fromex vivo and in vitro data, which has accumulated throughout the last few decades. We will also open the discussion as to whether the currently used categorization of lipedema stages is still sufficient and up-to-date for the accurate description of this enigmatic disease, whose name, strangely enough, does not match its pathologic correlate.
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Affiliation(s)
- Anna M. Ernst
- Department of Environment & Biodiversity, Paris Lodron University of Salzburg, 5020 Salzburg, Austria
| | - Hannelore Bauer
- Department of Environment & Biodiversity, Paris Lodron University of Salzburg, 5020 Salzburg, Austria
| | - Hans-Christian Bauer
- Department of Environment & Biodiversity, Paris Lodron University of Salzburg, 5020 Salzburg, Austria
- Institute for Tendon and Bone Regeneration, Paracelsus Medical University (PMU), 5020 Salzburg, Austria
| | - Marianne Steiner
- Department of Environment & Biodiversity, Paris Lodron University of Salzburg, 5020 Salzburg, Austria
| | - Anna Malfertheiner
- Department of Plastic Surgery and Hand Surgery, Klinikum rechts der Isar, Technical University of Munich (TUM), 81675 Munich, Germany
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4
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Scallan JP, Jannaway M. Lymphatic Vascular Permeability. Cold Spring Harb Perspect Med 2022; 12:a041274. [PMID: 35879102 PMCID: PMC9380735 DOI: 10.1101/cshperspect.a041274] [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] [Indexed: 11/24/2022]
Abstract
Blood vessels have a regulated permeability to fluid and solutes, which allows for the delivery of nutrients and signaling molecules to all cells in the body, a process essential to life. The lymphatic vasculature is the second network of vessels in the body, making up part of the immune system, yet is not typically thought of as having a permeability to fluid and solute. However, the major function of the lymphatic vasculature is to regulate tissue fluid balance to prevent edema, so lymphatic vessels must be permeable to absorb and transport fluid efficiently. Only recently were lymphatic vessels discovered to be permeable, which has had many functional implications. In this review, we will provide an overview of what is known about lymphatic vascular permeability, discuss the biophysical and signaling mechanisms regulating lymphatic permeability, and examine the disease relevance of this new property of lymphatic vessels.
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Affiliation(s)
- Joshua P Scallan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA
| | - Melanie Jannaway
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA
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5
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Yin Y, Zhu ZX, Li Z, Chen YS, Zhu WM. Role of mesenteric component in Crohn’s disease: A friend or foe? World J Gastrointest Surg 2021; 13:1536-1549. [PMID: 35070062 PMCID: PMC8727179 DOI: 10.4240/wjgs.v13.i12.1536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 08/01/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Crohn’s disease (CD) is a complex and relapsing gastrointestinal disease with mesenteric alterations. The mesenteric neural, vascular, and endocrine systems actively take part in the gut dysbiosis-adaptive immunity-mesentery-body axis, and this axis has been proven to be bidirectional. The abnormalities of morphology and function of the mesenteric component are associated with intestinal inflammation and disease progress of CD via responses to afferent signals, neuropeptides, lymphatic drainage, adipokines, and functional cytokines. The hypertrophy of mesenteric adipose tissue plays important roles in the pathogenesis of CD by secreting large amounts of adipokines and representing a rich source of proinflammatory or profibrotic cytokines. The vascular alteration, including angiogenesis and lymphangiogenesis, is concomitant in the disease course of CD. Of note, the enlarged and obstructed lymphatic vessels, which have been described in CD patients, are likely related to the early onset submucosa edema and being a cause of CD. The function of mesenteric lymphatics is influenced by endocrine of mesenteric nerves and adipocytes. Meanwhile, the structure of the mesenteric lymphatic vessels in hypertrophic mesenteric adipose tissue is mispatterned and ruptured, which can lead to lymph leakage. Leaky lymph factors can in turn stimulate adipose tissue to proliferate and effectively elicit an immune response. The identification of the role of mesentery and the crosstalk between mesenteric tissues in intestinal inflammation may shed light on understanding the underlying mechanism of CD and help explore new therapeutic targets.
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Affiliation(s)
- Yi Yin
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhen-Xing Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Zhun Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Yu-Sheng Chen
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
| | - Wei-Ming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu Province, China
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6
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Elz AS, Trevaskis NL, Porter CJH, Bowen JM, Prestidge CA. Smart design approaches for orally administered lipophilic prodrugs to promote lymphatic transport. J Control Release 2021; 341:676-701. [PMID: 34896450 DOI: 10.1016/j.jconrel.2021.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 12/03/2021] [Accepted: 12/04/2021] [Indexed: 12/22/2022]
Abstract
Challenges to effective delivery of drugs following oral administration has attracted growing interest over recent decades. Small molecule drugs (<1000 Da) are generally absorbed across the gastrointestinal tract into the portal blood and further transported to the systemic circulation via the liver. This can result in a significant reduction to the oral bioavailability of drugs that are metabolically labile and ultimately lead to ineffective exposure and treatment. Targeting drug delivery to the intestinal lymphatics is attracting increased attention as an alternative route of drug transportation providing multiple benefits. These include bypassing hepatic first-pass metabolism and selectively targeting disease reservoirs residing within the lymphatic system. The particular physicochemical requirements for drugs to be able to access the lymphatics after oral delivery include high lipophilicity (logP>5) and high long-chain triglyceride solubility (> 50 mg/g), properties required to enable drug association with the lipoprotein transport pathway. The majority of small molecule drugs, however, are not this lipophilic and therefore not substantially transported via the intestinal lymph. This has contributed to a growing body of investigation into prodrug approaches to deliver drugs to the lymphatic system by chemical manipulation. Optimised lipophilic prodrugs have the potential to increase lymphatic transport thereby improving oral pharmacokinetics via a reduction in first pass metabolism and may also target of disease-specific reservoirs within the lymphatics. This may provide advantages for current pharmacotherapy approaches for a wide array of pathological conditions, e.g. immune disease, cancer and metabolic disease, and also presents a promising approach for advanced vaccination strategies. In this review, specific emphasis is placed on medicinal chemistry strategies that have been successfully employed to design lipophilic prodrugs to deliberately enable lymphatic transport. Recent progress and opportunities in medicinal chemistry and drug delivery that enable new platforms for efficacious and safe delivery of drugs are critically evaluated.
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Affiliation(s)
- Aurelia S Elz
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
| | - Natalie L Trevaskis
- Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
| | - Christopher J H Porter
- Department of Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC 3052, Australia.
| | - Joanne M Bowen
- School of Biomedicine, The University of Adelaide, Adelaide, SA 5005, Australia.
| | - Clive A Prestidge
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
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7
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Qin L, Zhang H, Li B, Jiang Q, Lopez F, Min W, Zhou JH. CCM3 Loss-Induced Lymphatic Defect Is Mediated by the Augmented VEGFR3-ERK1/2 Signaling. Arterioscler Thromb Vasc Biol 2021; 41:2943-2960. [PMID: 34670407 PMCID: PMC8613000 DOI: 10.1161/atvbaha.121.316707] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Cerebral cavernous malformations (CCMs) can happen anywhere in the body, although they most commonly produce symptoms in the brain. The role of CCM genes in other vascular beds outside the brain and retina is not well-examined, although the 3 CCM-associated genes (CCM1, CCM2, and CCM3) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in lymphatics. Approach and Results: Mice with an inducible pan-endothelial cell (EC) or lymphatic EC deletion of Ccm3 (Pdcd10ECKO or Pdcd10LECKO) exhibit dilated lymphatic capillaries and collecting vessels with abnormal valve structure. Morphological alterations were correlated with lymphatic dysfunction in Pdcd10LECKO mice as determined by Evans blue dye and fluorescein isothiocyanate(FITC)-dextran transport assays. Pdcd10LECKO lymphatics had increased VEGFR3 (vascular endothelial growth factor receptor-3)-ERK1/2 (extracellular signal-regulated kinase 1/2) signaling with lymphatic hyperplasia. Mechanistic studies suggested that VEGFR3 is primarily regulated at a transcriptional level in Ccm3-deficient lymphatic ECs, in an NF-κB (nuclear factor κB)-dependent manner. CCM3 binds to importin alpha 2/KPNA2 (karyopherin subunit alpha 2), and a CCM3 deletion releases KPNA2 to activate NF-κB P65 by facilitating its nuclear translocation and P65-dependent VEGFR3 transcription. Moreover, increased VEGFR3 in lymphatic EC preferentially activates ERK1/2 signaling, which is critical for lymphatic EC proliferation. Importantly, inhibition of VEGFR3 or ERK1/2 rescued the lymphatic defects in structure and function. CONCLUSIONS Our data demonstrate that CCM3 deletion augments the VEGFR3-ERK1/2 signaling in lymphatic EC that drives lymphatic hyperplasia and malformation and warrant further investigation on the potential clinical relevance of lymphatic dysfunction in patients with CCM.
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MESH Headings
- Animals
- Apoptosis Regulatory Proteins/genetics
- Cells, Cultured
- Endothelial Cells/physiology
- Endothelium, Lymphatic/pathology
- Endothelium, Lymphatic/physiopathology
- Female
- Gene Deletion
- Hemangioma, Cavernous, Central Nervous System/pathology
- Hemangioma, Cavernous, Central Nervous System/physiopathology
- Hyperplasia
- MAP Kinase Signaling System/physiology
- Male
- Mice, Inbred Strains
- Models, Animal
- NF-kappa B/genetics
- Translocation, Genetic
- Vascular Endothelial Growth Factor Receptor-3/metabolism
- Mice
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Affiliation(s)
- Lingfeng Qin
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Haifeng Zhang
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Busu Li
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Quan Jiang
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Francesc Lopez
- Yale Center for Genome Analysis, Cancer Department of Genetics, Yale University School of Medicine, New Haven, CT
| | - Wang Min
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Jenny Huanjiao Zhou
- Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT
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8
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Molecular mechanisms of cyclic phosphatidic acid-induced lymphangiogenic actions in vitro. Microvasc Res 2021; 139:104273. [PMID: 34699844 DOI: 10.1016/j.mvr.2021.104273] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 11/21/2022]
Abstract
The lymphatic system plays important roles in various physiological and pathological phenomena. As a bioactive phospholipid, lysophosphatidic acid (LPA) has been reported to function as a lymphangiogenic factor as well as some growth factors, yet the involvement of phospholipids including LPA and its derivatives in lymphangiogenesis is not fully understood. In the present study, we have developed an in-vitro lymphangiogenesis model (termed a collagen sandwich model) by utilizing type-I collagen, which exists around the lymphatic endothelial cells of lymphatic capillaries in vivo. The collagen sandwich model has revealed that cyclic phosphatidic acid (cPA), and not LPA, augmented the tube formation of human dermal lymphatic endothelial cells (HDLECs). Both cPA and LPA increased the migration of HDLECs cultured on the collagen. As the gene expression of LPA receptor 6 (LPA6) was predominantly expressed in HDLECs, a siRNA experiment against LPA6 attenuated the cPA-mediated tube formation. A synthetic LPA1/3 inhibitor, Ki16425, suppressed the cPA-augmented tube formation and migration of the HDLECs, and the LPA-induced migration. The activity of Rho-associated protein kinase (ROCK) located at the downstream of the LPA receptors was augmented in both the cPA- and LPA-treated cells. A potent ROCK inhibitor, Y-27632, suppressed the cPA-dependent tube formation but not the migration of the HDLECs. Furthermore, cPA, but not LPA, augmented the gene expression of VE-cadherin and β-catenin in the HDLECs. These results provide novel evidence that cPA facilitates the capillary-like morphogenesis and the migration of HDLECs through LPA6/ROCK and LPA1/3 signaling pathways in concomitance with the augmentation of VE-cadherin and β-catenin expression. Thus, cPA is likely to be a potent lymphangiogenic factor for the initial lymphatics adjacent to type I collagen under physiological conditions.
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9
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Rockson SG. Comorbidity and Lymphatic Disease: The Lymphatic Continuum Re-Examined. Lymphat Res Biol 2021; 19:17-19. [PMID: 33625889 DOI: 10.1089/lrb.2021.0001] [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: 11/13/2022] Open
Abstract
It has now been ∼20 years since the original Lymphatic Continuum conference was convened, and this continuum has transitioned from a compelling concept to a reality. The explosive growth in our comprehension of lymphatic genetics, development, and function has expanded and modified our traditional views regarding what is, and is not, lymphatic disease. Groundbreaking investigations over the past decade have now defined a large and growing list of pathological conditions in which morphological or function lymphatic alterations can be identified. This list includes atherosclerosis and dyslipidemia, hypertension and other cardiovascular diseases, inflammation and inflammatory bowel disease, obesity, narrow angle glaucoma, and, most recently and compellingly, neurodegenerative disease. The sometimes overlapping but largely disparate nature of these various aforementioned disease categories suggests that the presence, or absence, of structural or functional lymphatic derangements may represent a previously unrecognized unifying influence in the maintenance of health and the promotion of disease. Future investigation of lymphatic mechanisms in disease will likely continue to elucidate the influences of lymphatic dysfunction, perhaps subtle, that can invest other, seemingly unrelated, diseases. In future, such discoveries will provide mechanistic insights and may potentiate the development of a new lymphatic-based approach to human disease diagnosis and therapeutics.
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Affiliation(s)
- Stanley G Rockson
- Department of Cardiovascular Medicine, Stanford Center for Lymphatic and Venous Disorders, Stanford University School of Medicine, Stanford, CA, USA
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10
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Cao E, Watt MJ, Nowell CJ, Quach T, Simpson JS, De Melo Ferreira V, Agarwal S, Chu H, Srivastava A, Anderson D, Gracia G, Lam A, Segal G, Hong J, Hu L, Phang KL, Escott ABJ, Windsor JA, Phillips ARJ, Creek DJ, Harvey NL, Porter CJH, Trevaskis NL. Mesenteric lymphatic dysfunction promotes insulin resistance and represents a potential treatment target in obesity. Nat Metab 2021; 3:1175-1188. [PMID: 34545251 DOI: 10.1038/s42255-021-00457-w] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 08/13/2021] [Indexed: 02/08/2023]
Abstract
Visceral adipose tissue (VAT) encases mesenteric lymphatic vessels and lymph nodes through which lymph is transported from the intestine and mesentery. Whether mesenteric lymphatics contribute to adipose tissue inflammation and metabolism and insulin resistance is unclear. Here we show that obesity is associated with profound and progressive dysfunction of the mesenteric lymphatic system in mice and humans. We find that lymph from mice and humans consuming a high-fat diet (HFD) stimulates lymphatic vessel growth, leading to the formation of highly branched mesenteric lymphatic vessels that 'leak' HFD-lymph into VAT and, thereby, promote insulin resistance. Mesenteric lymphatic dysfunction is regulated by cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-C-VEGF receptor (R)3 signalling. Lymph-targeted inhibition of COX-2 using a glyceride prodrug approach reverses mesenteric lymphatic dysfunction, visceral obesity and inflammation and restores glycaemic control in mice. Targeting obesity-associated mesenteric lymphatic dysfunction thus represents a potential therapeutic option to treat metabolic disease.
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Affiliation(s)
- Enyuan Cao
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
| | - Matthew J Watt
- Department of Physiology, University of Melbourne, Parkville, Victoria, Australia
| | - Cameron J Nowell
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Tim Quach
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Jamie S Simpson
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
- Puretech Health, Boston, MA, USA
| | - Vilena De Melo Ferreira
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Sonya Agarwal
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Hannah Chu
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Anubhav Srivastava
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Dovile Anderson
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Gracia Gracia
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Alina Lam
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Gabriela Segal
- Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
- Biological Optical Microscopy Platform, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia
| | - Jiwon Hong
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - Luojuan Hu
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Kian Liun Phang
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - Alistair B J Escott
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - John A Windsor
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
- HBP/Upper GI Unit, Department of General Surgery, Auckland City Hospital, Auckland, New Zealand
| | - Anthony R J Phillips
- Applied Surgery and Metabolism Laboratory, School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Surgical and Translational Research Centre, University of Auckland, Auckland, New Zealand
| | - Darren J Creek
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia
| | - Natasha L Harvey
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia
| | - Christopher J H Porter
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
| | - Natalie L Trevaskis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia.
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11
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Cho HK, Sung WJ, Lee YJ, Kwak SG, Kim KL. Two methods of extracorporeal shock-wave therapy in a rat model of secondary lymphedema: a pilot study. J Int Med Res 2021; 49:3000605211024473. [PMID: 34187210 PMCID: PMC8258771 DOI: 10.1177/03000605211024473] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives To compare the effectiveness of two methods of extracorporeal shock-wave therapy (ESWT) in a rat model of forelimb lymphedema, induced by axillary lymph node dissection. Methods Sprague–Dawley rats were randomly allocated to a group that received 500 ESWT shocks only in the lymphedematous forelimb (Forelimb/ESWT) and a group that received 300 ESWT shocks in the axilla and 200 shocks in the lymphedematous forelimb (Axilla+Forelimb/ESWT). The circumferences of each limb were then measured. Immunohistochemistry for a pan-endothelial marker (cluster of differentiation [CD]31) and lymphatic vessel endothelial hyaluronan receptor-1, and western blot analysis for vascular endothelial growth factor receptor-3 (VEGFR3) and VEGF-C were performed. Results The circumferences of the limbs showed significant effects of group and time following surgery. The circumferences at the carpal joint and 2.5 cm above were smallest in the naïve limbs, larger in the Axilla+Forelimb/ESWT group, and the largest in the control group. VEGFR3 tended to be expressed at a higher level in the Axilla+Forelimb/ESWT group (1.96-fold) than in the Forelimb/ESWT group (1.20-fold) versus the opposite non-edematous forelimbs, although this difference was not statistically significant. Conclusions These data suggest that ESWT protocols have differential effects on angiogenesis and lymphangiogenesis in lymphedematous limbs.
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Affiliation(s)
- Hee Kyung Cho
- Department of Physical Medicine and Rehabilitation, 65674Catholic University of Daegu School of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Woo Jung Sung
- Department of Pathology, 65674Catholic University of Daegu School of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Youn Ju Lee
- Department of Pharmacology, 65674Catholic University of Daegu School of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Sang Gyu Kwak
- Department of Medical Statistics, 65674Catholic University of Daegu School of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Kang Lip Kim
- Department of Physical Medicine and Rehabilitation, 65674Catholic University of Daegu School of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
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12
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Kumar R, Anand U, Priyadarshi RN. Lymphatic dysfunction in advanced cirrhosis: Contextual perspective and clinical implications. World J Hepatol 2021; 13:300-314. [PMID: 33815674 PMCID: PMC8006079 DOI: 10.4254/wjh.v13.i3.300] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/31/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
The lymphatic system plays a very important role in body fluid homeostasis, adaptive immunity, and the transportation of lipid and waste products. In patients with liver cirrhosis, capillary filtration markedly increases, primarily due to a rise in hydrostatic pressure, leading to enhanced production of lymph. Initially, lymphatic vasculature expansion helps to prevent fluid from accumulating by returning it back to the systemic circulation. However, the lymphatic functions become compromised with the progression of cirrhosis and, consequently, the lymphatic compensatory mechanism gets overwhelmed, contributing to the development and eventual worsening of ascites and edema. Neurohormonal changes, low-grade chronic inflammation, and compounding effects of predisposing factors such as old age, obesity, and metabolic syndrome appear to play a significant role in the lymphatic dysfunction of cirrhosis. Sustained portal hypertension can contribute to the development of intestinal lymphangiectasia, which may rupture into the intestinal lumen, resulting in the loss of protein, chylomicrons, and lymphocyte, with many clinical consequences. Rarely, due to high pressure, the rupture of the subserosal lymphatics into the abdomen results in the formation of chylous ascites. Despite being highly significant, lymphatic dysfunctions in cirrhosis have largely been ignored; its mechanistic pathogenesis and clinical implications have not been studied in depth. No recommendation exists for the diagnostic evaluation and therapeutic strategies, with respect to lymphatic dysfunction in patients with cirrhosis. This article discusses the perspectives and clinical implications, and provides insights into the management strategies for lymphatic dysfunction in patients with cirrhosis.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Utpal Anand
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Rajeev Nayan Priyadarshi
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Patna 801507, Bihar, India
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13
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Faerber G. Lymphstase und Fettgewebshypertrophie – Pathophysiologische Zusammenhänge und therapeutische Optionen. PHLEBOLOGIE 2021. [DOI: 10.1055/a-1389-0540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
ZusammenfassungAngeborene oder erworbene, iatrogene, traumatische oder postinfektiöse Störungen des Lymphabflusses führen aufgrund der Lymphstase im Laufe der Zeit zu Gewebeveränderungen wie Fibrosierung und vermehrter lokaler Fettgewebebildung. Häufig kommt es hierdurch zu einer extremen Volumenzunahme der betroffenen Extremität, die nicht durch das Lymphödem allein, sondern vor allem durch die massive Fettgewebshypertrophie bedingt ist. Lymphgefäße und Lymphknoten sind immer in Fettgewebe eingebettet. Dieses perilymphatische Fettgewebe ist essenziell für die lymphatische wie auch immunologische Funktion des Lymphsystems, da das Lymphsystem Fettsäuren als primäre Energiequelle nützt. Kommt es nach Lymphadenektomie und/oder Unterbrechung von Lymphgefäßen zur Lymphstase in der betroffenen Extremität, signalisiert diese einen gesteigerten Energiebedarf für die notwendige Immunantwort und die chronische Inflammation verursacht eine Überstimulation der Fettgewebsproliferation, um ausreichend Energie zur Verfügung stellen zu können. In der Folge kommt es zu weiteren pathophysiologischen Veränderungen, die die Drainagefunktion und damit die Lymphstase weiter verschlechtern. Es hat sich ein Circulus vitiosus aus Lymphstase, Fettgewebsproliferation und Fibrosierung entwickelt.Da die komplexe Entstauungstherapie diesen Zustand allein nicht wesentlich verbessern kann, kommen therapeutisch zusätzliche gewebereduzierende operative Verfahren, in erster Linie die Liposuktion, ggf. in Kombination mit mikrochirurgischen Operationstechniken, zum Einsatz.
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14
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Feng X, Travisano S, Pearson CA, Lien CL, Harrison MRM. The Lymphatic System in Zebrafish Heart Development, Regeneration and Disease Modeling. J Cardiovasc Dev Dis 2021; 8:21. [PMID: 33669620 PMCID: PMC7922492 DOI: 10.3390/jcdd8020021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 01/18/2023] Open
Abstract
Heart disease remains the single largest cause of death in developed countries, and novel therapeutic interventions are desperately needed to alleviate this growing burden. The cardiac lymphatic system is the long-overlooked counterpart of the coronary blood vasculature, but its important roles in homeostasis and disease are becoming increasingly apparent. Recently, the cardiac lymphatic vasculature in zebrafish has been described and its role in supporting the potent regenerative response of zebrafish heart tissue investigated. In this review, we discuss these findings in the wider context of lymphatic development, evolution and the promise of this system to open new therapeutic avenues to treat myocardial infarction and other cardiopathologies.
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Affiliation(s)
- Xidi Feng
- The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (X.F.); (S.T.)
| | - Stanislao Travisano
- The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (X.F.); (S.T.)
| | - Caroline A. Pearson
- Laboratory of Neurogenetics and Development, Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021, USA;
| | - Ching-Ling Lien
- The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; (X.F.); (S.T.)
- Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Michael R. M. Harrison
- Cardiovascular Research Institute, Weill Cornell Medical College, New York, NY 10021, USA
- Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10021, USA
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15
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Marcozzi C, Frattini A, Borgese M, Rossi F, Barone L, Solari E, Valli R, Gornati R. Paracrine effect of human adipose-derived stem cells on lymphatic endothelial cells. Regen Med 2020; 15:2085-2098. [PMID: 33201769 DOI: 10.2217/rme-2020-0071] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: The proposal of this study was to evaluate, in vitro, the potential paracrine effect of human adipose-derived stem cells (hASCs) to promote lymphangiogenesis in lymphatic endothelial cells isolated from rat diaphragmatic lymphatic vessels. Materials & methods: ELISA on VEGFA, VEGFC and IL6 in hASC-conditioned medium; LYVE1 immunostaining; and gene expression of PROX1, VEGFR3, VEGFC, VEGFA and IL6 were the methods used. Results: In 2D culture, hASC-conditioned medium was able to promote lymphatic endothelial cell survival, maintenance of endothelial cobblestone morphology and induction to form a vessel-like structure. Conclusion: The authors' results represent in vitro evidence of the paracrine effect of hASCs on lymphatic endothelial cells, suggesting the possible role of hASC-conditioned medium in developing new therapeutic approaches for lymphatic system-related dysfunction such as secondary lymphedema.
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Affiliation(s)
- Cristiana Marcozzi
- Department of Medicine & Surgery, Human Physiology, University of Insubria, 21100 Varese, Italy
| | - Annalisa Frattini
- Institute for Genetic & Biomedical Research, CNR, 20138 Milano, Italy.,Department of Medicine & Surgery, Human and Medical Genetics, University of Insubria, 21100 Varese, Italy
| | - Marina Borgese
- Department of Biotechnology & Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Federica Rossi
- Department of Biotechnology & Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Ludovica Barone
- Department of Biotechnology & Life Sciences, University of Insubria, 21100 Varese, Italy
| | - Eleonora Solari
- Department of Medicine & Surgery, Human Physiology, University of Insubria, 21100 Varese, Italy
| | - Roberto Valli
- Department of Medicine & Surgery, Human and Medical Genetics, University of Insubria, 21100 Varese, Italy
| | - Rosalba Gornati
- Department of Biotechnology & Life Sciences, University of Insubria, 21100 Varese, Italy
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16
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Semyachkina-Glushkovskaya O, Postnov D, Penzel T, Kurths J. Sleep as a Novel Biomarker and a Promising Therapeutic Target for Cerebral Small Vessel Disease: A Review Focusing on Alzheimer's Disease and the Blood-Brain Barrier. Int J Mol Sci 2020; 21:ijms21176293. [PMID: 32878058 PMCID: PMC7504101 DOI: 10.3390/ijms21176293] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/14/2020] [Accepted: 08/26/2020] [Indexed: 12/12/2022] Open
Abstract
Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline in elderly people and development of Alzheimer’s disease (AD). Blood–brain barrier (BBB) leakage is a key pathophysiological mechanism of amyloidal CSVD. Sleep plays a crucial role in keeping health of the central nervous system and in resistance to CSVD. The deficit of sleep contributes to accumulation of metabolites and toxins such as beta-amyloid in the brain and can lead to BBB disruption. Currently, sleep is considered as an important informative platform for diagnosis and therapy of AD. However, there are no effective methods for extracting of diagnostic information from sleep characteristics. In this review, we show strong evidence that slow wave activity (SWA) (0–0.5 Hz) during deep sleep reflects glymphatic pathology, the BBB leakage and memory deficit in AD. We also discuss that diagnostic and therapeutic targeting of SWA in AD might lead to be a novel era in effective therapy of AD. Moreover, we demonstrate that SWA can be pioneering non-invasive and bed–side technology for express diagnosis of the BBB permeability. Finally, we review the novel data about the methods of detection and enhancement of SWA that can be biomarker and a promising therapy of amyloidal CSVD and CSVD associated with the BBB disorders.
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Affiliation(s)
- Oxana Semyachkina-Glushkovskaya
- Department of Human and Animal Physiology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (D.P.); (T.P.); (J.K.)
- Physics Department, Humboldt University, Newtonstrasse 15, 12489 Berlin, Germany
- Correspondence: ; Tel.: +7-927-115-5157
| | - Dmitry Postnov
- Department of Human and Animal Physiology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (D.P.); (T.P.); (J.K.)
| | - Thomas Penzel
- Department of Human and Animal Physiology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (D.P.); (T.P.); (J.K.)
- Advanced Sleep Research GmbH, 12489 Berlin, Germany
- Charité-Universitätsmedizin Berlin, Sleep Medicine Center, Charitéplatz 1, 10117 Berlin, Germany
| | - Jürgen Kurths
- Department of Human and Animal Physiology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (D.P.); (T.P.); (J.K.)
- Physics Department, Humboldt University, Newtonstrasse 15, 12489 Berlin, Germany
- Potsdam Institute for Climate Impact Research, Telegrafenberg A31, 14473 Potsdam, Germany
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17
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Fang Y, Kaszuba T, Imoukhuede PI. Systems Biology Will Direct Vascular-Targeted Therapy for Obesity. Front Physiol 2020; 11:831. [PMID: 32760294 PMCID: PMC7373796 DOI: 10.3389/fphys.2020.00831] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/22/2020] [Indexed: 12/12/2022] Open
Abstract
Healthy adipose tissue expansion and metabolism during weight gain require coordinated angiogenesis and lymphangiogenesis. These vascular growth processes rely on the vascular endothelial growth factor (VEGF) family of ligands and receptors (VEGFRs). Several studies have shown that controlling vascular growth by regulating VEGF:VEGFR signaling can be beneficial for treating obesity; however, dysregulated angiogenesis and lymphangiogenesis are associated with several chronic tissue inflammation symptoms, including hypoxia, immune cell accumulation, and fibrosis, leading to obesity-related metabolic disorders. An ideal obesity treatment should minimize adipose tissue expansion and the advent of adverse metabolic consequences, which could be achieved by normalizing VEGF:VEGFR signaling. Toward this goal, a systematic investigation of the interdependency of vascular and metabolic systems in obesity and tools to predict personalized treatment ranges are necessary to improve patient outcomes through vascular-targeted therapies. Systems biology can identify the critical VEGF:VEGFR signaling mechanisms that can be targeted to regress adipose tissue expansion and can predict the metabolic consequences of different vascular-targeted approaches. Establishing a predictive, biologically faithful platform requires appropriate computational models and quantitative tissue-specific data. Here, we discuss the involvement of VEGF:VEGFR signaling in angiogenesis, lymphangiogenesis, adipogenesis, and macrophage specification – key mechanisms that regulate adipose tissue expansion and metabolism. We then provide useful computational approaches for simulating these mechanisms, and detail quantitative techniques for acquiring tissue-specific parameters. Systems biology, through computational models and quantitative data, will enable an accurate representation of obese adipose tissue that can be used to direct the development of vascular-targeted therapies for obesity and associated metabolic disorders.
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Affiliation(s)
- Yingye Fang
- Imoukhuede Systems Biology Laboratory, Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
| | - Tomasz Kaszuba
- Imoukhuede Systems Biology Laboratory, Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
| | - P I Imoukhuede
- Imoukhuede Systems Biology Laboratory, Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
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18
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Milasan A, Farhat M, Martel C. Extracellular Vesicles as Potential Prognostic Markers of Lymphatic Dysfunction. Front Physiol 2020; 11:476. [PMID: 32523544 PMCID: PMC7261898 DOI: 10.3389/fphys.2020.00476] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/20/2020] [Indexed: 12/21/2022] Open
Abstract
Despite significant efforts made to treat cardiovascular disease (CVD), more than half of cardiovascular events still occur in asymptomatic subjects devoid of traditional risk factors. These observations underscore the need for the identification of new biomarkers for the prevention of atherosclerosis, the main underlying cause of CVD. Extracellular vesicles (EVs) and lymphatic vessel function are emerging targets in this context. EVs are small vesicles released by cells upon activation or death that are present in several biological tissues and fluids, including blood and lymph. They interact with surrounding cells to transfer their cargo, and the complexity of their biological content makes these EVs potential key players in several chronic inflammatory settings. Many studies focused on the interaction of EVs with the most well-known players of atherosclerosis such as the vascular endothelium, smooth muscle cells and monocytes. However, the fate of EVs within the lymphatic network, a crucial route in the mobilization of cholesterol out the artery wall, is not known. In this review, we aim to bring forward evidence that EVs could be at the interplay between lymphatic function and atherosclerosis by summarizing the recent findings on the characterization of EVs in this setting.
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Affiliation(s)
- Andreea Milasan
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.,Montreal Heart Institute, Montreal, QC, Canada
| | - Maya Farhat
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.,Montreal Heart Institute, Montreal, QC, Canada
| | - Catherine Martel
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada.,Montreal Heart Institute, Montreal, QC, Canada
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19
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Kataru RP, Park HJ, Baik JE, Li C, Shin J, Mehrara BJ. Regulation of Lymphatic Function in Obesity. Front Physiol 2020; 11:459. [PMID: 32499718 PMCID: PMC7242657 DOI: 10.3389/fphys.2020.00459] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/16/2020] [Indexed: 12/15/2022] Open
Abstract
The lymphatic system has many functions, including macromolecules transport, fat absorption, regulation and modulation of adaptive immune responses, clearance of inflammatory cytokines, and cholesterol metabolism. Thus, it is evident that lymphatic function can play a key role in the regulation of a wide array of biologic phenomenon, and that physiologic changes that alter lymphatic function may have profound pathologic effects. Recent studies have shown that obesity can markedly impair lymphatic function. Obesity-induced pathologic changes in the lymphatic system result, at least in part, from the accumulation of inflammatory cells around lymphatic vessel leading to impaired lymphatic collecting vessel pumping capacity, leaky initial and collecting lymphatics, alterations in lymphatic endothelial cell (LEC) gene expression, and degradation of junctional proteins. These changes are important since impaired lymphatic function in obesity may contribute to the pathology of obesity in other organ systems in a feed-forward manner by increasing low-grade tissue inflammation and the accumulation of inflammatory cytokines. More importantly, recent studies have suggested that interventions that inhibit inflammatory responses, either pharmacologically or by lifestyle modifications such as aerobic exercise and weight loss, improve lymphatic function and metabolic parameters in obese mice. The purpose of this review is to summarize the pathologic effects of obesity on the lymphatic system, the cellular mechanisms that regulate these responses, the effects of impaired lymphatic function on metabolic syndrome in obesity, and the interventions that may improve lymphatic function in obesity.
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Affiliation(s)
- Raghu P Kataru
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Hyeong Ju Park
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jung Eun Baik
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Claire Li
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jinyeon Shin
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Babak J Mehrara
- Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States
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20
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Norden PR, Kume T. The Role of Lymphatic Vascular Function in Metabolic Disorders. Front Physiol 2020; 11:404. [PMID: 32477160 PMCID: PMC7232548 DOI: 10.3389/fphys.2020.00404] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022] Open
Abstract
In addition to its roles in the maintenance of interstitial fluid homeostasis and immunosurveillance, the lymphatic system has a critical role in regulating transport of dietary lipids to the blood circulation. Recent work within the past two decades has identified an important relationship between lymphatic dysfunction and patients with metabolic disorders, such as obesity and type 2 diabetes, in part characterized by abnormal lipid metabolism and transport. Utilization of several genetic mouse models, as well as non-genetic models of diet-induced obesity and metabolic syndrome, has demonstrated that abnormal lymphangiogenesis and poor collecting vessel function, characterized by impaired contractile ability and perturbed barrier integrity, underlie lymphatic dysfunction relating to obesity, diabetes, and metabolic syndrome. Despite the progress made by these models, the contribution of the lymphatic system to metabolic disorders remains understudied and new insights into molecular signaling mechanisms involved are continuously developing. Here, we review the current knowledge related to molecular mechanisms resulting in impaired lymphatic function within the context of obesity and diabetes. We discuss the role of inflammation, transcription factor signaling, vascular endothelial growth factor-mediated signaling, and nitric oxide signaling contributing to impaired lymphangiogenesis and perturbed lymphatic endothelial cell barrier integrity, valve function, and contractile ability in collecting vessels as well as their viability as therapeutic targets to correct lymphatic dysfunction and improve metabolic syndromes.
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Affiliation(s)
- Pieter R. Norden
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Tsutomu Kume
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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21
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Qian S, Pan J, Su Y, Tang Y, Wang Y, Zou Y, Zhao Y, Ma H, Zhang Y, Liu Y, Guo L, Tang QQ. BMPR2 promotes fatty acid oxidation and protects white adipocytes from cell death in mice. Commun Biol 2020; 3:200. [PMID: 32350411 PMCID: PMC7190840 DOI: 10.1038/s42003-020-0928-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 04/01/2020] [Indexed: 12/11/2022] Open
Abstract
Adipocyte cell death is pathologically involved in both obesity and lipodystrophy. Inflammation and pro-inflammatory cytokines are generally regarded as inducers for adipocyte apoptosis, but whether some innate defects affect their susceptibility to cell death has not been extensively studied. Here, we found bone morphogenetic protein receptor type 2 (BMPR2) knockout adipocytes were prone to cell death, which involved both apoptosis and pyroptosis. BMPR2 deficiency in adipocytes inhibited phosphorylation of perilipin, a lipid-droplet-coating protein, and impaired lipolysis when stimulated by tumor necrosis factor (TNFα), which lead to failure of fatty acid oxidation and oxidative phosphorylation. In addition, impaired lipolysis was associated with mitochondria-mediated apoptosis and pyroptosis as well as elevated inflammation. These results suggest that BMPR2 is important for maintaining the functional integrity of adipocytes and their ability to survive when interacting with inflammatory factors, which may explain why adipocytes among individuals show discrepancy for death responses in inflammatory settings.
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Affiliation(s)
- Shuwen Qian
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Jiabao Pan
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Yan Su
- Department of Orthopaedics, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 200032, Shanghai, China
| | - Yan Tang
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Yina Wang
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Ying Zou
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Yaxin Zhao
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Hong Ma
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Youyou Zhang
- Center for Research on Reproduction & Women's Health, University of Pennsylvania, Philadelphia, PA, USA
| | - Yang Liu
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Liang Guo
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Qi-Qun Tang
- The Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, and Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
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22
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Semyachkina-Glushkovskaya O, Abdurashitov A, Dubrovsky A, Klimova M, Agranovich I, Terskov A, Shirokov A, Vinnik V, Kuzmina A, Lezhnev N, Blokhina I, Shnitenkova A, Tuchin V, Rafailov E, Kurths J. Photobiomodulation of lymphatic drainage and clearance: perspective strategy for augmentation of meningeal lymphatic functions. BIOMEDICAL OPTICS EXPRESS 2020; 11:725-734. [PMID: 32206394 PMCID: PMC7041454 DOI: 10.1364/boe.383390] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 12/25/2019] [Accepted: 01/05/2020] [Indexed: 06/10/2023]
Abstract
There is a hypothesis that augmentation of the drainage and clearing function of the meningeal lymphatic vessels (MLVs) might be a promising therapeutic target for preventing neurological diseases. Here we investigate mechanisms of photobiomodulation (PBM, 1267 nm) of lymphatic drainage and clearance. Our results obtained at optical coherence tomography (OCT) give strong evidence that low PBM doses (5 and 10 J/cm2) stimulate drainage function of the lymphatic vessels via vasodilation (OCT data on the mesenteric lymphatics) and stimulation of lymphatic clearance (OCT data on clearance of gold nanorods from the brain) that was supported by confocal imaging of clearance of FITC-dextran from the cortex via MLVs. We assume that PBM-mediated relaxation of the lymphatic vessels can be possible mechanisms underlying increasing the permeability of the lymphatic endothelium that allows molecules transported by the lymphatic vessels and explain PBM stimulation of lymphatic drainage and clearance. These findings open new strategies for the stimulation of MLVs functions and non-pharmacological therapy of brain diseases.
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Affiliation(s)
| | - Arkady Abdurashitov
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
- Tomsk State University, 36 Lenin’s Ave., Tomsk 634050, Russian Federation, Russia
| | | | - Maria Klimova
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
| | - Ilana Agranovich
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
| | - Andrey Terskov
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
| | - Alexander Shirokov
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
- Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, Entusiastov Str. 13, Saratov 410049, Russia
| | - Valeria Vinnik
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
| | - Anna Kuzmina
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
| | - Nikita Lezhnev
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
| | - Inna Blokhina
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
| | | | - Valery Tuchin
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
- Tomsk State University, 36 Lenin’s Ave., Tomsk 634050, Russian Federation, Russia
- Institute of Precision Mechanics and Control of the Russian Academy of Sciences, 24 Rabochaya Str., Saratov 410028, Russian Federation, Russia
| | - Edik Rafailov
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
- Optoelectronics and Biomedical Photonics Group, Aston University, Birmingham, B4 7ET, UK
| | - Jurgen Kurths
- Saratov State University, Astrakhanskaya Str. 83, Saratov 410012, Russia
- Humboldt University, Newtonstrasse 15, 12489 Berlin, Germany Potsdam, Germany
- Institute for Climate Impact Research, Telegrafenberg A31, 14473 Potsdam, Germany
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23
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Chang CW, Seibel AJ, Song JW. Application of microscale culture technologies for studying lymphatic vessel biology. Microcirculation 2019; 26:e12547. [PMID: 30946511 DOI: 10.1111/micc.12547] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 03/04/2019] [Accepted: 04/02/2019] [Indexed: 12/17/2022]
Abstract
Immense progress in microscale engineering technologies has significantly expanded the capabilities of in vitro cell culture systems for reconstituting physiological microenvironments that are mediated by biomolecular gradients, fluid transport, and mechanical forces. Here, we examine the innovative approaches based on microfabricated vessels for studying lymphatic biology. To help understand the necessary design requirements for microfluidic models, we first summarize lymphatic vessel structure and function. Next, we provide an overview of the molecular and biomechanical mediators of lymphatic vessel function. Then we discuss the past achievements and new opportunities for microfluidic culture models to a broad range of applications pertaining to lymphatic vessel physiology. We emphasize the unique attributes of microfluidic systems that enable the recapitulation of multiple physicochemical cues in vitro for studying lymphatic pathophysiology. Current challenges and future outlooks of microscale technology for studying lymphatics are also discussed. Collectively, we make the assertion that further progress in the development of microscale models will continue to enrich our mechanistic understanding of lymphatic biology and physiology to help realize the promise of the lymphatic vasculature as a therapeutic target for a broad spectrum of diseases.
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Affiliation(s)
- Chia-Wen Chang
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio
| | - Alex J Seibel
- Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, Ohio
| | - Jonathan W Song
- Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, Ohio.,The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
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Amamizu H, Matsumoto Y, Morosawa S, Ohyama K, Uzuka H, Hirano M, Nishimiya K, Gokon Y, Watanabe-Asaka T, Hayashi M, Miyata S, Kamei T, Kawai Y, Shimokawa H. Cardiac Lymphatic Dysfunction Causes Drug-Eluting Stent–Induced Coronary Hyperconstricting Responses in Pigs In Vivo. Arterioscler Thromb Vasc Biol 2019; 39:741-753. [DOI: 10.1161/atvbaha.119.312396] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Objective—
We have previously demonstrated that coronary adventitial inflammation plays important roles in the pathogenesis of coronary vasomotion abnormalities, including drug-eluting stent (DES)–induced coronary hyperconstricting responses. Importantly, the adventitia also harbors lymphatic vessels, which may prevent inflammation by transporting extravasated fluid and inflammatory cells. We thus aimed to examine the roles of coronary adventitial lymphatic vessels in the pathogenesis of DES-induced coronary hyperconstricting responses in a porcine model in vivo.
Approach and Results—
We performed 2 experimental studies. In protocol 1, 15 pigs were divided into 3 groups with or without DES and with bare metal stent. Nonstented sites 20 mm apart from stent implantation also were examined. In the protocol 2, 12 pigs were divided into 2 groups with or without lymphatic vessels ligation followed by DES implantation at 2 weeks later (n=6 each). We performed coronary angiography 4 weeks after DES implantation, followed by immunohistological analysis. In protocol 1, the number and the caliber of lymphatic vessels were greater at only the DES edges after 4 more weeks. In protocol 2, coronary hyperconstricting responses were further enhanced in the lymphatic vessels ligation group associated with adventitial inflammation, Rho-kinase activation, and less adventitial lymphatic vessels formation. Importantly, there were significant correlations among these inflammation-related changes and enhanced coronary vasoconstricting responses.
Conclusions—
These results provide evidence that cardiac lymphatic vessel dysfunction plays important roles in the pathogenesis of coronary vasoconstrictive responses in pigs in vivo.
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Affiliation(s)
- Hirokazu Amamizu
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuharu Matsumoto
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Susumu Morosawa
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuma Ohyama
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hironori Uzuka
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michinori Hirano
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kensuke Nishimiya
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yusuke Gokon
- Department of Gastroenterological Surgery (Y.G., T.K.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomomi Watanabe-Asaka
- Division of Physiology, Tohoku Medical and Pharmaceutical University (T.W.-A., M. Hayashi, Y.K.), Sendai, Japan
| | - Moyuru Hayashi
- Division of Physiology, Tohoku Medical and Pharmaceutical University (T.W.-A., M. Hayashi, Y.K.), Sendai, Japan
| | - Satoshi Miyata
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Gastroenterological Surgery (Y.G., T.K.), Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshiko Kawai
- Division of Physiology, Tohoku Medical and Pharmaceutical University (T.W.-A., M. Hayashi, Y.K.), Sendai, Japan
| | - Hiroaki Shimokawa
- From the Department of Cardiovascular Medicine (H.A., Y.M., S. Morosawa, K.O., H.U., M. Hirano, K.N., S. Miyata, H.S.), Tohoku University Graduate School of Medicine, Sendai, Japan
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25
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Chakraborty A, Barajas S, Lammoglia GM, Reyna AJ, Morley TS, Johnson JA, Scherer PE, Rutkowski JM. Vascular Endothelial Growth Factor-D (VEGF-D) Overexpression and Lymphatic Expansion in Murine Adipose Tissue Improves Metabolism in Obesity. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:924-939. [PMID: 30878136 DOI: 10.1016/j.ajpath.2018.12.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 11/13/2018] [Accepted: 12/11/2018] [Indexed: 12/18/2022]
Abstract
Obese adipose tissue expansion is an inflammatory process that results in dysregulated lipolysis, increased circulating lipids, ectopic lipid deposition, and systemic insulin resistance. Lymphatic vessels provide a route of fluid, macromolecule, and immune cell clearance, and lymphangiogenesis increases this capability. Indeed, inflammation-associated lymphangiogenesis is critical in resolving acute and chronic inflammation, but it is largely absent in obese adipose tissue. Enhancing adipose tissue lymphangiogenesis could, therefore, improve metabolism in obesity. To test this hypothesis, transgenic mice with doxycycline-inducible expression of murine vascular endothelial growth factor (VEGF)-D under a tightly controlled Tet-On promoter were crossed with adipocyte-specific adiponectin-reverse tetracycline-dependent transactivator mice (Adipo-VD) to stimulate adipose tissue-specific lymphangiogenesis during 16-week high-fat diet-induced obesity. Adipose VEGF-D overexpression induced de novo lymphangiogenesis in murine adipose tissue, and obese Adipo-VD mice exhibited enhanced glucose clearance, lower insulin levels, and reduced liver triglycerides. On β-3 adrenergic stimulation, Adipo-VD mice exhibited more rapid and increased glycerol flux from adipose tissue, suggesting that the lymphatics are a potential route of glycerol clearance. Resident macrophage crown-like structures were scarce and total F4/80+ macrophages were reduced in obese Adipo-VD s.c. adipose tissue with evidence of increased immune trafficking from the tissue. Augmenting VEGF-D signaling and lymphangiogenesis specifically in adipose tissue, therefore, reduces obesity-associated immune accumulation and improves metabolic responsiveness.
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Affiliation(s)
- Adri Chakraborty
- Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M College of Medicine, College Station
| | - Sheridan Barajas
- Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M College of Medicine, College Station
| | - Gabriela M Lammoglia
- Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M College of Medicine, College Station
| | - Andrea J Reyna
- Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M College of Medicine, College Station
| | - Thomas S Morley
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Joshua A Johnson
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Joseph M Rutkowski
- Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M College of Medicine, College Station.
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26
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Duyur Cakıt B, Pervane Vural S, Ayhan FF. Complex Decongestive Therapy in Breast Cancer-Related Lymphedema: Does Obesity Affect the Outcome Negatively? Lymphat Res Biol 2019; 17:45-50. [DOI: 10.1089/lrb.2017.0086] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
- Burcu Duyur Cakıt
- Division of Oncologic Rehabilitation and Lymphedema, Department of Physical Medicine and Rehabilitation, Ankara Training and Research Hospital, Ankara, Turkey
| | - Secil Pervane Vural
- Division of Oncologic Rehabilitation and Lymphedema, Department of Physical Medicine and Rehabilitation, Ankara Training and Research Hospital, Ankara, Turkey
| | - F. Figen Ayhan
- Division of Oncologic Rehabilitation and Lymphedema, Department of Physical Medicine and Rehabilitation, Ankara Training and Research Hospital, Ankara, Turkey
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Breslin JW, Yang Y, Scallan JP, Sweat RS, Adderley SP, Murfee WL. Lymphatic Vessel Network Structure and Physiology. Compr Physiol 2018; 9:207-299. [PMID: 30549020 PMCID: PMC6459625 DOI: 10.1002/cphy.c180015] [Citation(s) in RCA: 204] [Impact Index Per Article: 29.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The lymphatic system is comprised of a network of vessels interrelated with lymphoid tissue, which has the holistic function to maintain the local physiologic environment for every cell in all tissues of the body. The lymphatic system maintains extracellular fluid homeostasis favorable for optimal tissue function, removing substances that arise due to metabolism or cell death, and optimizing immunity against bacteria, viruses, parasites, and other antigens. This article provides a comprehensive review of important findings over the past century along with recent advances in the understanding of the anatomy and physiology of lymphatic vessels, including tissue/organ specificity, development, mechanisms of lymph formation and transport, lymphangiogenesis, and the roles of lymphatics in disease. © 2019 American Physiological Society. Compr Physiol 9:207-299, 2019.
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Affiliation(s)
- Jerome W. Breslin
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Ying Yang
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Joshua P. Scallan
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Richard S. Sweat
- Department of Biomedical Engineering, Tulane University, New Orleans, LA
| | - Shaquria P. Adderley
- Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - W. Lee Murfee
- Department of Biomedical Engineering, University of Florida, Gainesville, FL
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Abstract
BACKGROUND Lymphedema occurs commonly in cancer survivors. It is crucial to properly assess cancer patients in order to distinguish lymphedema from general edema and to initiate evidence based treatment. PURPOSE To provide evidence based recommendations for screening, evaluating, and treating lymphedema and to establish the role of the nurse in the care of patients with lymphedema. METHODOLOGY Comprehensive overview with narrative literature review of evidence based lymphedema diagnosis and treatment. FINDINGS Cancer-related edema represents numerous complex conditions. A variety of interventions are needed to address prevention, early detection, patient education, and effective treatment. CONCLUSION Lymphedema treatment is complex and multimodal, and is provided by an interdisciplinary team of properly trained professionals. Nurses play a major role in evaluating, treating and educating patients on the signs and symptoms of cancer-related edema and patient self-management. CLINICAL IMPLICATIONS Evidence-based assessment and treatment should be initiated early to improve outcomes and quality of life in patients with cancer-related lymphedema.
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29
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Lin Y, Leung G, Louie D, Bogoslowski A, Ross J, Kubes P, von der Weid PY, Liao S. Perinodal Adipose Tissue Participates in Immune Protection through a Lymphatic Vessel-Independent Route. THE JOURNAL OF IMMUNOLOGY 2018; 201:296-305. [PMID: 29760196 DOI: 10.4049/jimmunol.1800151] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 04/27/2018] [Indexed: 12/15/2022]
Abstract
Lymphatic vessels remove and transport excess interstitial fluid to lymph nodes (LNs) for fluid balance and immune protection. LNs are typically surrounded by perinodal adipose tissue (PAT). However, PAT is a blood vessel-rich but lymphatic-rare tissue; therefore, how excess fluid in PAT is removed remains unclear. Using C57BL/6 mice, fluorescent dye tracing and transmission electron microscopy results suggest that fluid in PAT can travel to the LN via collagen I+ channels (PAT-LN conduits), merge into a collagen-rich space between the PAT and LN capsule (PAT-LN sinus), and may enter the LN via the LN capsule-associated conduits. This newly identified route of fluid flow allows fluid to enter the draining LN even when the afferent lymphatic vessels are blocked, indicating that fluid trafficking in PAT-LN conduits is not dependent on functional lymphatic vessels. Similar to lymphatic vessels, PAT-LN conduits can deliver Ags to the LN for immune protection. Additionally, Staphylococcus aureus from intradermal or i.v. infection may use PAT-LN conduits to infect PAT and stimulate PAT immune protection. Our studies revealed a new route of material exchange between PAT and the LN. Ag accumulation and bacterial infection in PAT demonstrate that PAT not only provides energy and regulatory factors, but can also directly participate in immune protection, indicating a new immune function of PAT for host immunity.
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Affiliation(s)
- Yujia Lin
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.,Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin 150086, China; and
| | - Glory Leung
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Dante Louie
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Ania Bogoslowski
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - James Ross
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Paul Kubes
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Pierre-Yves von der Weid
- Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Shan Liao
- Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada;
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30
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Ruhl T, Storti G, Pallua N. Proliferation, Metabolic Activity, and Adipogenic Differentiation of Human Preadipocytes Exposed to 2 Surfactants In Vitro. J Pharm Sci 2018; 107:1408-1415. [DOI: 10.1016/j.xphs.2017.12.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/24/2017] [Accepted: 12/14/2017] [Indexed: 01/09/2023]
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31
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Agko M, Ciudad P, Chen HC. Staged surgical treatment of extremity lymphedema with dual gastroepiploic vascularized lymph node transfers followed by suction-assisted lipectomy-A prospective study. J Surg Oncol 2018; 117:1148-1156. [PMID: 29355987 DOI: 10.1002/jso.24969] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 12/08/2017] [Indexed: 01/03/2023]
Affiliation(s)
- Mouchammed Agko
- Department of Plastic Surgery; China Medical University Hospital; Taichung Taiwan
| | - Pedro Ciudad
- Department of Plastic Surgery; China Medical University Hospital; Taichung Taiwan
- Department of Biological Science and Technology; China Medical University; Taichung Taiwan
| | - Hung-Chi Chen
- Department of Plastic Surgery; China Medical University Hospital; Taichung Taiwan
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32
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Keith L, Rowsemitt C, Richards LG. Lifestyle Modification Group for Lymphedema and Obesity Results in Significant Health Outcomes. Am J Lifestyle Med 2017; 14:420-428. [PMID: 33281522 DOI: 10.1177/1559827617742108] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 10/19/2017] [Accepted: 10/21/2017] [Indexed: 11/17/2022] Open
Abstract
This study investigated whether a lifestyle modification program that encouraged a ketogenic diet (KD) for participants with lymphedema and obesity would reduce weight and limb volume and improve quality of life. A total of 12 participants with lymphedema and obesity (mean body mass index = 38.38; SD = 7.02) were enrolled in a lifestyle modification group. The timespan from baseline data collection to 30-day follow-up was 18 weeks. Retention rate was 83.3%. Data were analyzed with repeated-measures ANOVA and Pearson correlation. Participants demonstrated statistically significant improvement in most outcome measures. Mean weight loss was 5.18 kg-F(4, 36) = 11.17; P < .001-or 4.8% of mean baseline weight. The average limb volume reduction was 698.9 ml-F(4, 36) = 9.4; P < .001-and was positively correlated with weight loss (r = 0.8; P = .005). There appeared to be a tendency for participants who used a KD (n = 6) to demonstrate superior results in most outcome measures compared with those who did not use the diet (n = 4), although the sample size of the 2 groups was too small to report definitive results. This lifestyle modification program provided insight into the possible value of a KD for obesity and lymphedema management.
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Affiliation(s)
- Leslyn Keith
- Central Coast Lymphedema Therapy, San Luis Obispo, California (LK).,Comprehensive Weight Management, A Nursing Corp, Templeton, California (CR).,Department of Occupational and Recreational Therapies, University of Utah, Salt Lake City, Utah (LGR)
| | - Carol Rowsemitt
- Central Coast Lymphedema Therapy, San Luis Obispo, California (LK).,Comprehensive Weight Management, A Nursing Corp, Templeton, California (CR).,Department of Occupational and Recreational Therapies, University of Utah, Salt Lake City, Utah (LGR)
| | - Lorie G Richards
- Central Coast Lymphedema Therapy, San Luis Obispo, California (LK).,Comprehensive Weight Management, A Nursing Corp, Templeton, California (CR).,Department of Occupational and Recreational Therapies, University of Utah, Salt Lake City, Utah (LGR)
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Chang H, Park SO, Jin US, Hong KY. Characterization of two distinct lipomas: a comparative analysis from surgical perspective. J Plast Surg Hand Surg 2017; 52:178-184. [PMID: 29022421 DOI: 10.1080/2000656x.2017.1386665] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND Lipomas are common benign soft tissue tumors that are well-circumscribed and encapsulated. However, adipose masses that are not demarcated from the surrounding fat are often encountered. Two distinct types of lipomas were analyzed from surgical perspective. METHODS Thirty patients were enrolled after lipoma excision and diagnosed with either encapsulated (n = 20) or non-encapsulated lipoma (n = 10). Comparison of clinical variables, histologic analyses and characterization of the lipoma adipose-derived stem cells (ASCs) between the two lipomas were performed. RESULTS Non-encapsulated lipomas were associated with older age at operation, larger tumor and increased seroma formation. The density of lymphatic vessels and gene expressions related to lymphatic vessel, inflammation and proliferation were increased in non-encapsulated lipoma. ASCs of non-encapsulated lipoma showed enhanced proliferation when cultured with serum. CONCLUSIONS Non-encapsulated lipomas and their ASCs showed distinct lymphatic histology and cellular response. These findings elucidated the pathogenesis and pathophysiology of lipomas.
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Affiliation(s)
- Hak Chang
- a Department of Plastic and Reconstructive Surgery , Seoul National University College of Medicine , Seoul , Korea
| | - Seong Oh Park
- a Department of Plastic and Reconstructive Surgery , Seoul National University College of Medicine , Seoul , Korea
| | - Ung Sik Jin
- a Department of Plastic and Reconstructive Surgery , Seoul National University College of Medicine , Seoul , Korea
| | - Ki Yong Hong
- b Department of Plastic and Reconstructive Surgery , Dongguk University Medical Center , Goyang , Korea
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Cucchi F, Rossmeislova L, Simonsen L, Jensen MR, Bülow J. A vicious circle in chronic lymphoedema pathophysiology? An adipocentric view. Obes Rev 2017; 18:1159-1169. [PMID: 28660651 DOI: 10.1111/obr.12565] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/07/2017] [Accepted: 04/25/2017] [Indexed: 12/11/2022]
Abstract
Chronic lymphoedema is a disease caused by a congenital or acquired damage to the lymphatic system and characterized by complex chains of pathophysiologic events such as lymphatic fluid stasis, chronic inflammation, lymphatic vessels impairment, adipose tissue deposition and fibrosis. These events seem to maintain and reinforce themselves through a positive feedback loop: regardless of the initial cause of lymphatic stasis, the dysfunctional adipose tissue and its secretion products can worsen lymphatic vessels' function, aggravating lymph leakage and stagnation, which can promote further adipose tissue deposition and fibrosis, similar to what may happen in obesity. In addition to the current knowledge about the tight and ancestral interrelation between immunity system and metabolism, there is evidence for similarities between obesity-related and lymphatic damage-induced lymphoedema. Together, these observations indicate strong reciprocal relationship between lymphatics and adipose tissue and suggest a possible key role of the adipocyte in the pathophysiology of chronic lymphoedema's vicious circle.
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Affiliation(s)
- F Cucchi
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
| | - L Rossmeislova
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - L Simonsen
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
| | - M R Jensen
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
| | - J Bülow
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark.,Department of Biomedical Sciences, Copenhagen University, Denmark
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35
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Bharath LP, Ip BC, Nikolajczyk BS. Adaptive Immunity and Metabolic Health: Harmony Becomes Dissonant in Obesity and Aging. Compr Physiol 2017; 7:1307-1337. [PMID: 28915326 DOI: 10.1002/cphy.c160042] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Adipose tissue (AT) is the primary energy reservoir organ, and thereby plays a critical role in energy homeostasis and regulation of metabolism. AT expands in response to chronic overnutrition or aging and becomes a major source of inflammation that has marked influence on systemic metabolism. The chronic, sterile inflammation that occurs in the AT during the development of obesity or in aging contributes to onset of devastating diseases such as insulin resistance, diabetes, and cardiovascular pathologies. Numerous studies have shown that inflammation in the visceral AT of humans and animals is a critical trigger for the development of metabolic syndrome. This work underscores the well-supported conclusion that the inflammatory immune response and metabolic pathways in the AT are tightly interwoven by multiple layers of relatively conserved mechanisms. During the development of diet-induced obesity or age-associated adiposity, cells of the innate and the adaptive immune systems infiltrate and proliferate in the AT. Macrophages, which dominate AT-associated immune cells in mouse models of obesity, but are less dominant in obese people, have been studied extensively. However, cells of the adaptive immune system, including T cells and B cells, contribute significantly to AT inflammation, perhaps more in humans than in mice. Lymphocytes regulate recruitment of innate immune cells into AT, and produce cytokines that influence the helpful-to-harmful inflammatory balance that, in turn, regulates organismal metabolism. This review describes inflammation, or more precisely, metabolic inflammation (metaflammation) with an eye toward the AT and the roles lymphocytes play in regulation of systemic metabolism during obesity and aging. © 2017 American Physiological Society. Compr Physiol 7:1307-1337, 2017.
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Affiliation(s)
- Leena P Bharath
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Blanche C Ip
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.,Department of Molecular Pharmacology, Physiology and Biotechnology, Center of Biomedical Engineering, Brown University, Providence, Rhode Island, USA
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36
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Betterman KL, Harvey NL. The lymphatic vasculature: development and role in shaping immunity. Immunol Rev 2016; 271:276-92. [PMID: 27088921 DOI: 10.1111/imr.12413] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The lymphatic vasculature is an integral component of the immune system. Lymphatic vessels are a key highway via which immune cells are trafficked, serving not simply as a passive route of transport, but to actively shape and coordinate immune responses. Reciprocally, immune cells provide signals that impact the growth, development, and activity of the lymphatic vasculature. In addition to immune cell trafficking, lymphatic vessels are crucial for fluid homeostasis and lipid absorption. The field of lymphatic vascular research is rapidly expanding, fuelled by rapidly advancing technology that has enabled the manipulation and imaging of lymphatic vessels, together with an increasing recognition of the involvement of lymphatic vessels in a myriad of human pathologies. In this review we provide an overview of the genetic pathways and cellular processes important for development and maturation of the lymphatic vasculature, discuss recent work revealing important roles for the lymphatic vasculature in directing immune cell traffic and coordinating immune responses and highlight the involvement of lymphatic vessels in a range of pathological settings.
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Affiliation(s)
- Kelly L Betterman
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
| | - Natasha L Harvey
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.,School of Medicine, University of Adelaide, Adelaide, SA, Australia
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Ciccone V, Monti M, Antonini G, Mattoli L, Burico M, Marini F, Maidecchi A, Morbidelli L. Efficacy of AdipoDren® in Reducing Interleukin-1-Induced Lymphatic Endothelial Hyperpermeability. J Vasc Res 2016; 53:255-268. [PMID: 27923233 DOI: 10.1159/000452798] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 10/23/2016] [Indexed: 12/18/2022] Open
Abstract
Lymphatic leakage can be seen as a detrimental phenomenon associated with fluid retention and deposition as well as gain of weight. Moreover, lymphatic dysfunction is associated with an inflammatory environment and can be a substrate for other health conditions. A number of treatments can ameliorate lymphatic vasculature: natural substances have been used as treatment options particularly suitable for their consolidated effectiveness and safety profile. Here we report the protective effect of AdipoDren®, an association of a series of plant-derived natural complexes, on lymphatic endothelium permeability promoted by interleukin-1 beta (IL-1β) and the associated molecular mechanisms. AdipoDren® demonstrated a protective effect on dermal lymphatic endothelial cell permeability increased by IL-1β. Reduced permeability was due to the maintenance of tight junctions and cell-cell localisation of occludin and zonula occludens-1 (ZO-1). Moreover, AdipoDren® reduced the expression of the inflammatory key element cyclooxygenase-2 (COX-2), while not altering the levels of endothelial and inducible nitric oxide synthases (eNOS and iNOS). The upregulation of antioxidant enzymatic systems (catalase and superoxide dismutase-1, SOD-1) and the downregulation of pro-oxidant markers (p22 phox subunit of NADPH oxidase) were also evident. In conclusion, AdipoDren® would be useful to ameliorate conditions of altered lymphatic vasculature and to support the physiological functionality of the lymphatic endothelium.
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Affiliation(s)
- Valerio Ciccone
- Department of Life Sciences, University of Siena, Siena, Italy
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Munger SJ, Davis MJ, Simon AM. Defective lymphatic valve development and chylothorax in mice with a lymphatic-specific deletion of Connexin43. Dev Biol 2016; 421:204-218. [PMID: 27899284 DOI: 10.1016/j.ydbio.2016.11.017] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 11/22/2016] [Accepted: 11/22/2016] [Indexed: 12/17/2022]
Abstract
Lymphatic valves (LVs) are cusped luminal structures that permit the movement of lymph in only one direction and are therefore critical for proper lymphatic vessel function. Congenital valve aplasia or agenesis can, in some cases, be a direct cause of lymphatic disease. Knowledge about the molecular mechanisms operating during the development and maintenance of LVs may thus aid in the establishment of novel therapeutic approaches to treat lymphatic disorders. In this study, we examined the role of Connexin43 (Cx43), a gap junction protein expressed in lymphatic endothelial cells (LECs), during valve development. Mouse embryos with a null mutation in Cx43 (Gja1) were previously shown to completely lack mesenteric LVs at embryonic day 18. However, interpreting the phenotype of Cx43-/- mice was complicated by the fact that global deletion of Cx43 causes perinatal death due to heart defects during embryogenesis. We have now generated a mouse model (Cx43∆LEC) with a lymphatic-specific ablation of Cx43 and show that the absence of Cx43 in LECs causes a delay (rather than a complete block) in LV initiation, an increase in immature valves with incomplete leaflet elongation, a reduction in the total number of valves, and altered lymphatic capillary patterning. The physiological consequences of these lymphatic changes were leaky valves, insufficient lymph transport and reflux, and a high incidence of lethal chylothorax. These results demonstrate that the expression of Cx43 is specifically required in LECs for normal development of LVs.
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Affiliation(s)
| | - Michael J Davis
- Dept. of Medical Pharmacology & Physiology, University of Missouri School of Medicine, Columbia, MO, USA.
| | - Alexander M Simon
- Department of Physiology, University of Arizona, Tucson AZ 85724, USA.
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Scallan JP, Zawieja SD, Castorena-Gonzalez JA, Davis MJ. Lymphatic pumping: mechanics, mechanisms and malfunction. J Physiol 2016; 594:5749-5768. [PMID: 27219461 PMCID: PMC5063934 DOI: 10.1113/jp272088] [Citation(s) in RCA: 260] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 05/17/2016] [Indexed: 12/19/2022] Open
Abstract
A combination of extrinsic (passive) and intrinsic (active) forces move lymph against a hydrostatic pressure gradient in most regions of the body. The effectiveness of the lymph pump system impacts not only interstitial fluid balance but other aspects of overall homeostasis. This review focuses on the mechanisms that regulate the intrinsic, active contractions of collecting lymphatic vessels in relation to their ability to actively transport lymph. Lymph propulsion requires not only robust contractions of lymphatic muscle cells, but contraction waves that are synchronized over the length of a lymphangion as well as properly functioning intraluminal valves. Normal lymphatic pump function is determined by the intrinsic properties of lymphatic muscle and the regulation of pumping by lymphatic preload, afterload, spontaneous contraction rate, contractility and neural influences. Lymphatic contractile dysfunction, barrier dysfunction and valve defects are common themes among pathologies that directly involve the lymphatic system, such as inherited and acquired forms of lymphoedema, and pathologies that indirectly involve the lymphatic system, such as inflammation, obesity and metabolic syndrome, and inflammatory bowel disease.
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Affiliation(s)
- Joshua P Scallan
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
| | - Scott D Zawieja
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
| | | | - Michael J Davis
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA.
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Wong LL, Lee NG, Amarnani D, Choi CJ, Bielenberg DR, Freitag SK, D'Amore PA, Kim LA. Orbital Angiogenesis and Lymphangiogenesis in Thyroid Eye Disease: An Analysis of Vascular Growth Factors with Clinical Correlation. Ophthalmology 2016; 123:2028-36. [PMID: 27423310 DOI: 10.1016/j.ophtha.2016.05.052] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 05/31/2016] [Accepted: 05/31/2016] [Indexed: 01/12/2023] Open
Abstract
PURPOSE The human orbit is an environment that is vulnerable to inflammation and edema in the setting of autoimmune thyroid disease. Our study investigated the tenet that orbital adipose tissue lacks lymphatic vessels and analyzed the clinicopathologic differences between patients with acute and chronic thyroid eye disease (TED). The underlying molecular mediators of blood and lymphatic vessel formation within the orbital fat also were evaluated. DESIGN Retrospective cohort study. PARTICIPANTS The study included fat specimens from 26 orbits of 15 patients with TED undergoing orbital decompression. Orbital fat specimens from patients without TED as well as cadaveric orbital fat served as controls. METHODS Tissue specimens were processed as formalin-fixed, paraffin-embedded sections or frozen cryosections for immunohistochemistry. Total RNA was extracted and analyzed via quantitative (real-time) reverse-transcription polymerase chain reaction. Clinicopathologic correlation was made by determining the clinical activity score (CAS) of each patient with TED. MAIN OUTCOME MEASURES Samples were examined for vascular and lymphatic markers including podoplanin, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and cluster of differentiation 31 (CD31) by immunohistochemistry, as well as for mRNA levels of vascular endothelial growth factor (VEGF), VEGF receptors, semaphorin 3F, neuropilin 1, neuropilin 2, podoplanin, and LYVE-1 by quantitative (real-time) reverse-transcription polymerase chain reaction. RESULTS Clinicopathologic correlation revealed increased staining of CD31-positive blood vessels in patients with acute TED with a CAS more than 4, as well as rare staining of podoplanin-positive lymphatic vessels within acutely inflamed orbital fat tissue. Additionally, quantitative (real-time) reverse-transcription polymerase chain reaction analysis demonstrated increased expression of VEGF receptor (VEGFR) 2 as well as VEGF signaling molecules VEGF-A, VEGF-C, and VEGF-D. CONCLUSIONS In acute TED, compared with chronic TED and control orbital fat, there is increased blood vessel density, suggesting neovascularization and rare lymphatic vessels suggestive of limited lymphangiogenesis. This proangiogenic and prolymphangiogenic microenvironment is likely the result of the increased expression of VEGFR-2, VEGF-A, VEGF-C, and VEGF-D. These findings imply that orbital edema in acute TED may be mediated, in part, by both the formation of new, immature blood vessels and the formation of lymphatic capillaries that are functionally incapable of draining interstitial fluid.
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Affiliation(s)
- Lindsay L Wong
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
| | - Nahyoung Grace Lee
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Ophthalmic Plastic Surgery, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
| | - Dhanesh Amarnani
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
| | - Catherine J Choi
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Ophthalmic Plastic Surgery, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
| | - Diane R Bielenberg
- Department of Surgery, Harvard Medical School, Children's Hospital of Boston, Boston, Massachusetts
| | - Suzanne K Freitag
- Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Ophthalmic Plastic Surgery, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts
| | - Patricia A D'Amore
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
| | - Leo A Kim
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
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Corazza M, Tardella FM, Ferrari C, Catorci A. Tall Grass Invasion After Grassland Abandonment Influences the Availability of Palatable Plants for Wild Herbivores: Insight into the Conservation of the Apennine Chamois Rupicapra pyrenaica ornata. ENVIRONMENTAL MANAGEMENT 2016; 57:1247-1261. [PMID: 26899738 DOI: 10.1007/s00267-016-0679-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 02/10/2016] [Indexed: 06/05/2023]
Abstract
Invasion of the tall grass Brachypodium genuense was observed in an area of the central Apennines (Italy) where the population size of Apennine chamois (Rupicapra pyrenaica ornata) was in strong decline. Since this dominant tall grass threatens biodiversity and forage quality, our hypothesis was that B. genuense abundance influenced that of palatable species for the chamois, depending on their functional traits and distribution patterns. Our sampling design used plots of 10 × 10 m and 1 × 1 m to investigate the plant community level and fine-scale interactions. We analyzed data using correlation, generalized linear models, and redundancy analyses. We found that B. genuense can reach high abundance values on the deepest soils. Its high cover value influences plant community composition by competitive exclusion of subordinate species and suppression of functional features because of temporal or spatial niche overlap. This leads to low cover of palatable species at a fine scale, and to poor pasture quality for chamois at a wider scale. Therefore, we postulated that B. genuense invasion, enhanced by long-term grazing cessation, may reduce the availability of palatable plants for Apennine chamois, especially below the potential timberline (1900-2000 m a.s.l.). The high abundance of B. genuense may amplify the effect of other negative factors, such as competition with red deer (Cervus elaphus) and climate change, in restricting the suitable habitat of the Apennine chamois to the higher sectors of the central Apennines. Thus, we suggested that B. genuense spread should be monitored carefully and plans to control its invasion should be implemented.
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Affiliation(s)
- Marcello Corazza
- Department of Biological, Geological and Environmental Sciences, University of Bologna, Via Irnerio 42, 40126, Bologna, Italy
| | - Federico Maria Tardella
- Research Unit of Plant Biodiversity and Ecosystem Management, School of Bioscience and Veterinary Medicine, University of Camerino, Via Pontoni 5, 62032, Camerino, MC, Italy.
| | - Carlo Ferrari
- Department of Biological, Geological and Environmental Sciences, University of Bologna, Via Irnerio 42, 40126, Bologna, Italy
| | - Andrea Catorci
- Research Unit of Plant Biodiversity and Ecosystem Management, School of Bioscience and Veterinary Medicine, University of Camerino, Via Pontoni 5, 62032, Camerino, MC, Italy
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Li Y, Zhu W, Zuo L, Shen B. The Role of the Mesentery in Crohn's Disease: The Contributions of Nerves, Vessels, Lymphatics, and Fat to the Pathogenesis and Disease Course. Inflamm Bowel Dis 2016; 22:1483-95. [PMID: 27167572 DOI: 10.1097/mib.0000000000000791] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Crohn's disease (CD) is a complex gastrointestinal disorder involving multiple levels of cross talk between the immunological, neural, vascular, and endocrine systems. The current dominant theory in CD is based on the unidirectional axis of dysbiosis-innate immunity-adaptive immunity-mesentery-body system. Emerging clinical evidence strongly suggests that the axis be bidirectional. The morphologic and/or functional abnormalities in the mesenteric structures likely contribute to the disease progression of CD, to a less extent the disease initiation. In addition to adipocytes, mesentery contains nerves, blood vessels, lymphatics, stromal cells, and fibroblasts. By the secretion of adipokines that have endocrine functions, the mesenteric fat tissue exerts its activity in immunomodulation mainly through response to afferent signals, neuropeptides, and functional cytokines. Mesenteric nerves are involved in the pathogenesis and prognosis of CD mainly through neuropeptides. In addition to angiogenesis observed in CD, lymphatic obstruction, remodeling, and impaired contraction maybe a cause and consequence of CD. Lymphangiogenesis and angiogenesis play a concomitant role in the progress of chronic intestinal inflammation. Finally, the interaction between neuropeptides, adipokines, and vascular and lymphatic endothelia leads to adipose tissue remodeling, which makes the mesentery an active participator, not a bystander, in the disease initiation and precipitation CD. The identification of the role of mesentery, including the structure and function of mesenteric nerves, vessels, lymphatics, and fat, in the intestinal inflammation in CD has important implications in understanding its pathogenesis and clinical management.
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Affiliation(s)
- Yi Li
- *Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China; and †Center for Inflammatory Bowel Disease, Digestive Disease Institute, The Cleveland Clinic Foundation, Cleveland, Ohio
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43
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Sedger LM, Tull DL, McConville MJ, De Souza DP, Rupasinghe TWT, Williams SJ, Dayalan S, Lanzer D, Mackie H, Lam TC, Boyages J. Lipidomic Profiling of Adipose Tissue Reveals an Inflammatory Signature in Cancer-Related and Primary Lymphedema. PLoS One 2016; 11:e0154650. [PMID: 27182733 PMCID: PMC4868287 DOI: 10.1371/journal.pone.0154650] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Accepted: 04/15/2016] [Indexed: 12/12/2022] Open
Abstract
Cancer-related and primary lymphedema (LE) are associated with the production of adipose tissue (AT). Nothing is known, however, about the lipid-based molecules that comprise LE AT. We therefore analyzed lipid molecules in lipoaspirates and serum obtained from LE patients, and compared them to lipoaspirates from cosmetic surgery patients and healthy control cohort serum. LE patient serum analysis demonstrated that triglycerides, HDL- and LDL-cholesterol and lipid transport molecules remained within the normal range, with no alterations in individual fatty acids. The lipidomic analysis also identified 275 lipid-based molecules, including triacylglycerides, diacylglycerides, fatty acids and phospholipids in AT oil and fat. Although the majority of lipid molecules were present in a similar abundance in LE and non-LE samples, there were several small changes: increased C20:5-containing triacylglycerides, reduced C10:0 caprinic and C24:1 nervonic acids. LE AT oil also contained a signature of increased cyclopropane-type fatty acids and inflammatory mediators arachidonic acid and ceramides. Interestingly C20:5 and C22:6 omega-3-type lipids are increased in LE AT, correlating with LE years. Hence, LE AT has a normal lipid profile containing a signature of inflammation and omega-3-lipids. It remains unclear, however, whether these differences reflect a small-scale global metabolic disturbance or effects within localised inflammatory foci.
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Affiliation(s)
- Lisa M. Sedger
- Department of Clinical Medicine, Faculty of Medicine & Health Science, Macquarie University, Sydney, NSW, Australia
- * E-mail:
| | - Dedreia L. Tull
- Metabolomics Australia, Bio21 Institute, The University of Melbourne, Melbourne, VIC, Australia
| | - Malcolm J. McConville
- Metabolomics Australia, Bio21 Institute, The University of Melbourne, Melbourne, VIC, Australia
| | - David P. De Souza
- Metabolomics Australia, Bio21 Institute, The University of Melbourne, Melbourne, VIC, Australia
| | | | - Spencer J. Williams
- Metabolomics Australia, Bio21 Institute, The University of Melbourne, Melbourne, VIC, Australia
- School of Chemistry, The University of Melbourne, Melbourne, VIC, Australia
| | - Saravanan Dayalan
- Metabolomics Australia, Bio21 Institute, The University of Melbourne, Melbourne, VIC, Australia
| | - Daniel Lanzer
- Daniel Lanzer Clinic, Malvern, Melbourne, VIC, Australia
| | - Helen Mackie
- Macquarie University Hospital, North Ryde, Sydney, NSW, Australia
| | - Thomas C. Lam
- Macquarie University Hospital, North Ryde, Sydney, NSW, Australia
| | - John Boyages
- Department of Clinical Medicine, Faculty of Medicine & Health Science, Macquarie University, Sydney, NSW, Australia
- Macquarie University Hospital, North Ryde, Sydney, NSW, Australia
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Kassis T, Yarlagadda SC, Kohan AB, Tso P, Breedveld V, Dixon JB. Postprandial lymphatic pump function after a high-fat meal: a characterization of contractility, flow, and viscosity. Am J Physiol Gastrointest Liver Physiol 2016; 310:G776-89. [PMID: 26968208 PMCID: PMC4888550 DOI: 10.1152/ajpgi.00318.2015] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 03/04/2016] [Indexed: 01/31/2023]
Abstract
Dietary lipids are transported from the intestine through contractile lymphatics. Chronic lipid loads can adversely affect lymphatic function. However, the acute lymphatic pump response in the mesentery to a postprandial lipid meal has gone unexplored. In this study, we used the rat mesenteric collecting vessel as an in vivo model to quantify the effect of lipoproteins on vessel function. Lipid load was continuously monitored by using the intensity of a fluorescent fatty-acid analog, which we infused along with a fat emulsion through a duodenal cannula. The vessel contractility was simultaneously quantified. We demonstrated for the first time that collecting lymphatic vessels respond to an acute lipid load by reducing pump function. High lipid levels decreased contraction frequency and amplitude. We also showed a strong tonic response through a reduction in the end-diastolic and systolic diameters. We further characterized the changes in flow rate and viscosity and showed that both increase postprandially. In addition, shear-mediated Ca(2+) signaling in lymphatic endothelial cells differed when cultured with lipoproteins. Together these results show that the in vivo response could be both shear and lipid mediated and provide the first evidence that high postprandial lipid has an immediate negative effect on lymphatic function even in the acute setting.
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Affiliation(s)
- Timothy Kassis
- 1Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, Georgia; ,2School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, Georgia;
| | - Sri Charan Yarlagadda
- 4School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia; and
| | - Alison B. Kohan
- 5Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Patrick Tso
- 5Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Victor Breedveld
- 4School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Georgia; and
| | - J. Brandon Dixon
- 1Parker H. Petit Institute for Bioengineering & Bioscience, Georgia Institute of Technology, Atlanta, Georgia; ,3George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia;
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45
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Dam V, Sikder T, Santosa S. From neutrophils to macrophages: differences in regional adipose tissue depots. Obes Rev 2016; 17:1-17. [PMID: 26667065 DOI: 10.1111/obr.12335] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Revised: 09/01/2015] [Accepted: 09/23/2015] [Indexed: 12/27/2022]
Abstract
Currently, we do not fully understand the underlying mechanisms of how regional adiposity promotes metabolic dysregulation. As adipose tissue expands, there is an increase in chronic systemic low-grade inflammation due to greater infiltration of immune cells and production of cytokines. This chronic inflammation is thought to play a major role in the development of metabolic complications and disease such as insulin resistance and diabetes. We know that different adipose tissue depots contribute differently to the risk of metabolic disease. People who have an upper body fat distribution around the abdomen are at greater risk of disease than those who tend to store fat in their lower body around the hips and thighs. Thus, it is conceivable that adipose tissue depots contribute differently to the inflammatory milieu as a result of varied infiltration of immune cell types. In this review, we describe the role and function of major resident immune cells in the development of adipose tissue inflammation and discuss their regional differences in the context of metabolic disease risk. We find that although initial studies have found regional differences, a more comprehensive understanding of how immune cells interrupt adipose tissue homeostasis is needed.
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Affiliation(s)
- V Dam
- Department of Exercise Science, Concordia University, Montreal, QC, Canada.,Nutrition, Obesity, and Metabolism Lab, PERFORM Centre, Concordia University, Montreal, QC, Canada
| | - T Sikder
- Department of Exercise Science, Concordia University, Montreal, QC, Canada.,Nutrition, Obesity, and Metabolism Lab, PERFORM Centre, Concordia University, Montreal, QC, Canada
| | - S Santosa
- Department of Exercise Science, Concordia University, Montreal, QC, Canada.,Nutrition, Obesity, and Metabolism Lab, PERFORM Centre, Concordia University, Montreal, QC, Canada
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46
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Trevaskis NL, Kaminskas LM, Porter CJH. From sewer to saviour — targeting the lymphatic system to promote drug exposure and activity. Nat Rev Drug Discov 2015; 14:781-803. [DOI: 10.1038/nrd4608] [Citation(s) in RCA: 378] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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47
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Basta D, Latinovic O, Lafferty MK, Sun L, Bryant J, Lu W, Caccuri F, Caruso A, Gallo R, Garzino-Demo A. Angiogenic, lymphangiogenic and adipogenic effects of HIV-1 matrix protein p17. Pathog Dis 2015; 73:ftv062. [PMID: 26333571 DOI: 10.1093/femspd/ftv062] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2015] [Indexed: 11/13/2022] Open
Abstract
Lymphangiogenesis and concurrent angiogenesis are essential in supporting proliferation and survival of AIDS-related lymphomas, which are often metastatic. In vitro studies suggest a candidate angiogienic and lymphangiogenic factor encoded by HIV: the matrix protein p17. p17 accumulates in lymph nodes of patients even when they are undergoing highly active antiretroviral therapy. p17 has been found to affect immune cells, and recent data showed that a variant p17, called S75X, induces cell growth by triggering MAPK/ERK and PI3K/AKT pathways. We tested the in vivo angiogenic activity of p17 by injecting it in Matrigel plugs in nude mice. Plugs were retrieved 7 days after injection, and assessed macroscopically, and by light and confocal microscopy. Our data revealed that both reference and S75X variant p17 promote angiogenesis and lymphangiogenesis in vivo. Our results suggest that the induction of angiogenesis and lymphangiogenesis by HIV-1 p17 may generate a favorable microenvironment that could trigger tumor growth and maintenance. Moreover, the presence of adipocytes infiltration observed at the histological level suggests a possible interplay between angiogenesis, lymphangiogenesis and adipogenesis. These findings offer new opportunities for the development of treatment strategies to combat HIV-related cancers.
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Affiliation(s)
- Daniele Basta
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA Microbiology Section, Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy
| | - Olga Latinovic
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA Department of Microbiology and Immunology, Baltimore, MD 21201, USA
| | - Mark K Lafferty
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Lingling Sun
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Joseph Bryant
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Wuyuan Lu
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA Department of Biochemistry and Molecular Biology, Baltimore, MD 21201, USA
| | - Francesca Caccuri
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Arnaldo Caruso
- Microbiology Section, Department of Molecular and Translational Medicine, University of Brescia, Brescia 25123, Italy
| | - Robert Gallo
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Alfredo Garzino-Demo
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA Department of Microbiology and Immunology, Baltimore, MD 21201, USA Department of Molecular Medicine, University of Padova, 35123, Italy
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Tran CD, Grice DM, Wade B, Kerr CA, Bauer DC, Li D, Hannan GN. Gut permeability, its interaction with gut microflora and effects on metabolic health are mediated by the lymphatics system, liver and bile acid. Future Microbiol 2015; 10:1339-53. [PMID: 26234760 DOI: 10.2217/fmb.15.54] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
There is evidence to link obesity (and metabolic syndrome) with alterations in gut permeability and microbiota. The underlying mechanisms have been questioned and have prompted this review. We propose that the gut barrier function is a primary driver in maintaining metabolic health with poor health being linked to ‘gut leakiness'. This review will highlight changes in intestinal permeability and how it may change gut microflora and subsequently affect metabolic health by influencing the functioning of major bodily organs/organ systems: the lymphatic system, liver and pancreas. We also discuss the likelihood that metabolic syndrome undergoes a cyclic worsening facilitated by an increase in intestinal permeability leading to gut dysbiosis, culminating in ongoing poor health leading to further exacerbated gut leakiness.
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Affiliation(s)
- Cuong D Tran
- CSIRO Food & Nutrition Flagship, Adelaide, SA 5000, Australia
| | - Desma M Grice
- CSIRO Food & Nutrition Flagship, North Ryde, NSW 2113, Australia
| | - Ben Wade
- CSIRO Biosecurity Flagship, Geelong, VIC 3219, Australia
| | - Caroline A Kerr
- CSIRO Food & Nutrition Flagship, North Ryde, NSW 2113, Australia
| | - Denis C Bauer
- CSIRO Digital Productivity & Services Flagship, North Ryde, NSW 1670, Australia
| | - Dongmei Li
- CSIRO Food & Nutrition Flagship, North Ryde, NSW 2113, Australia
| | - Garry N Hannan
- CSIRO Food & Nutrition Flagship, North Ryde, NSW 2113, Australia
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Souza-Smith FM, Siggins RW, Molina PE. Mesenteric Lymphatic-Perilymphatic Adipose Crosstalk: Role in Alcohol-Induced Perilymphatic Adipose Tissue Inflammation. Alcohol Clin Exp Res 2015; 39:1380-7. [PMID: 26147204 DOI: 10.1111/acer.12796] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 05/29/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND The digestive tract lymphatics transport approximately two-thirds of all lymph produced in the body and have a key role in mucosal immunity through their contribution to antigen transport and immune cell trafficking. Mesenteric lymphatic pumping function integrity is critical for maintaining homeostasis and lipid transport. We previously demonstrated that acute alcohol intoxication (AAI) increases mesenteric lymphatic amplitude of contraction and ejection fraction, enhancing the ability of the lymphatic vessels to pump lymph. AAI has been shown to disrupt intestinal barrier integrity, which would be expected to increase the endotoxin content of mesenteric lymph. In this study, we tested the prediction that AAI increases lymphatic permeability directly affecting perilymphatic adipose tissue (PLAT) milieu. METHODS Male Sprague Dawley rats received an intragastric infusion of 2.5 g/kg of alcohol. Isovolumic administration of water (vehicle) served as control. PLAT was isolated for the determination of Evans Blue extravasation (permeability), cytokine content, and immunohistochemistry for inflammatory cell infiltration at 30 minutes and 24 hours after alcohol administration. RESULTS PLAT isolated from AAI animals had greater Evans Blue concentrations and cytokine expression (24 hours post-AAI) and mast cell and neutrophil density than that isolated from controls. AAI resulted in significantly higher plasma lipopolysaccharide (endotoxin) levels, lower plasma adiponectin levels (at 30 minutes), and unchanged plasma visfatin levels. CONCLUSIONS The data indicate that AAI induces mesenteric lymphatic hyperpermeability, promotes PLAT inflammatory milieu and disrupts the systemic adipokine profile. These findings suggest an association between alcohol-induced lymphatic hyperpermeability and early manifestations of metabolic dysfunction as a result of alcohol abuse. We propose that crosstalk between lymph and PLAT results in adipose inflammation and adipokine dysregulation during AAI.
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Affiliation(s)
- Flavia M Souza-Smith
- Department of Physiology, Alcohol and Drug Abuse Center of Excellence, LSUHSC, New Orleans, Louisiana
| | - Robert W Siggins
- Department of Physiology, Alcohol and Drug Abuse Center of Excellence, LSUHSC, New Orleans, Louisiana
| | - Patricia E Molina
- Department of Physiology, Alcohol and Drug Abuse Center of Excellence, LSUHSC, New Orleans, Louisiana
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50
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Kuan EL, Ivanov S, Bridenbaugh EA, Victora G, Wang W, Childs EW, Platt AM, Jakubzick CV, Mason RJ, Gashev AA, Nussenzweig M, Swartz MA, Dustin ML, Zawieja DC, Randolph GJ. Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. THE JOURNAL OF IMMUNOLOGY 2015; 194:5200-10. [PMID: 25917096 DOI: 10.4049/jimmunol.1500221] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/22/2015] [Indexed: 12/31/2022]
Abstract
Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. In this study, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived Ags by these cells supported recall T cell responses in the fat and also generated Ag-bearing DCs for emigration into adjacent lymph nodes (LNs). Enhanced recruitment of DCs to inflammation-reactive LNs significantly relied on adipose tissue DCs to maintain sufficient numbers of Ag-bearing DCs as the LN expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for Ag transport into the adjacent LN.
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Affiliation(s)
- Emma L Kuan
- Department of Gene and Cell Medicine, Graduate Program in Immunology and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
| | - Stoyan Ivanov
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Eric A Bridenbaugh
- Division of Lymphatic Biology, Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, Texas A&M Health Science Center College of Medicine, Temple, TX 76504
| | - Gabriel Victora
- Program in Molecular Pathogenesis, Skirball Institute for Biomolecular Medicine, The Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University School of Medicine, New York, NY 10016
| | - Wei Wang
- Division of Lymphatic Biology, Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, Texas A&M Health Science Center College of Medicine, Temple, TX 76504
| | - Ed W Childs
- Department of Surgery, Cardiovascular Research Institute, Texas A&M Health Science Center College of Medicine, Temple, TX 76504
| | - Andrew M Platt
- Department of Gene and Cell Medicine, Graduate Program in Immunology and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029
| | | | - Robert J Mason
- Department of Medicine, National Jewish Health, Denver, CO 80206
| | - Anatoliy A Gashev
- Division of Lymphatic Biology, Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, Texas A&M Health Science Center College of Medicine, Temple, TX 76504
| | - Michel Nussenzweig
- Laboratory of Molecular Immunology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065; and
| | - Melody A Swartz
- Institute of Bioengineering, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland
| | - Michael L Dustin
- Program in Molecular Pathogenesis, Skirball Institute for Biomolecular Medicine, The Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University School of Medicine, New York, NY 10016
| | - David C Zawieja
- Division of Lymphatic Biology, Department of Systems Biology and Translational Medicine, Cardiovascular Research Institute, Texas A&M Health Science Center College of Medicine, Temple, TX 76504
| | - Gwendalyn J Randolph
- Department of Gene and Cell Medicine, Graduate Program in Immunology and Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110;
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