Abstract 377: The Role of Impaired Lymphatic Drainage in Cardiac Transplantation

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Sydney C Ginn ◽  
Lanfang Wang ◽  
Rebecca D Levit
Keyword(s):  
Chronic Rejection ◽  
Cardiac Transplantation ◽  
Transplant Rejection ◽  
Lymphatic Drainage ◽  
Tissue Fluid ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
Cardiac Allografts ◽  
Pro Inflammatory Cytokines

Functional lymphatic drainage inherently modulates cardiac function by maintaining the immune response and tissue-fluid homeostasis. During cardiac transplantation, the lymphatic collecting vessels are severed at the time of heart excision and not surgically reconstructed in the recipient. The consequence resulting from impaired lymphatic drainage in transplanted hearts is unknown. We hypothesize disruption of lymphatic drainage potentiates chronic inflammation by impeding the egress of immune cells and pro-inflammatory cytokines out of the myocardium exacerbating transplant rejection. Methods: Banked human allograft biopsies were utilized to retrospectively evaluate lymphatic differences between patients that did and did not develop chronic transplant rejection from 1 week to 5 years after surgery. Immunofluorescence staining permitted quantification of normalized lymphatic vessel number and area throughout the lifespan of each cardiac allograft (n=24). Autopsy patients with non-cardiac related fatalities served as controls to delineate normal cardiac lymphatic distribution (n=6). Results: Patients without chronic rejection displayed an initial presence of lymphatic vasculature that steadily declined (n=12), while patients with chronic rejection exhibited a delayed increase in lymphatic development (n=12). Conclusions: These data show significant differences in lymphatic area between patients with and without chronic transplant rejection at critical timepoints, suggesting delayed lymphangiogenesis may correlate with rejection. Translational Impact: These preliminary human data support further investigation into lymphatic-modifying therapeutics to prolong the life of cardiac allografts.

scholarly journals Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe

2020 ◽  
Vol 6 (50) ◽  
pp. eabc2697
Author(s):  
Kim Pin Yeo ◽  
Hwee Ying Lim ◽  
Chung Hwee Thiam ◽  
Syaza Hazwany Azhar ◽  
Caris Tan ◽  
...  
Keyword(s):  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Lymphatic Transport ◽  
Atherosclerotic Plaques ◽  
Tissue Fluid ◽  
Atherosclerosis Progression ◽  
Lymphatic Vasculature ◽  
Lesion Regression ◽  
Transport Of Macromolecules

A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance. Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood. We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe. Disruption of aortic lymph flow by lymphatic ligation promotes adventitial inflammation and development of atherosclerotic plaque in hypercholesterolemic mice and inhibits ezetimibe-induced atherosclerosis regression. Thus, progression of atherosclerotic plaques may result not only from increased entry of atherogenic factors into the arterial wall but also from reduced lymphatic clearance of these factors as a result of aortic lymph stasis. Our findings suggest that promoting lymphatic drainage might be effective for treating atherosclerosis.

scholarly journals Lymphatic endothelial-cell expressed ACKR3 is dispensable for postnatal lymphangiogenesis and lymphatic drainage function in mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249068
Author(s):  
Elena C. Sigmund ◽  
Lilian Baur ◽  
Philipp Schineis ◽  
Jorge Arasa ◽  
Victor Collado-Diaz ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Knockout Mouse ◽  
Lymphatic Endothelial Cell ◽  
Peptide Hormone ◽  
Lymphatic Drainage ◽  
Adult Mice ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
And Function

Atypical chemokine receptor ACKR3 (formerly CXCR7) is a scavenging receptor that has recently been implicated in murine lymphatic development. Specifically, ACKR3-deficiency was shown to result in lymphatic hyperplasia and lymphedema, in addition to cardiac hyperplasia and cardiac valve defects leading to embryonic lethality. The lymphatic phenotype was attributed to a lymphatic endothelial cell (LEC)-intrinsic scavenging function of ACKR3 for the vascular peptide hormone adrenomedullin (AM), which is also important during postnatal lymphangiogenesis. In this study, we investigated the expression of ACKR3 in the lymphatic vasculature of adult mice and its function in postnatal lymphatic development and function. We show that ACKR3 is widely expressed in mature lymphatics and that it exerts chemokine-scavenging activity in cultured murine skin-derived LECs. To investigate the role of LEC-expressed ACKR3 in postnatal lymphangiogenesis and function during adulthood, we generated and validated a lymphatic-specific, inducible ACKR3 knockout mouse. Surprisingly, in contrast to the reported involvement of ACKR3 in lymphatic development, our analyses revealed no contribution of LEC-expressed ACKR3 to postnatal lymphangiogenesis, lymphatic morphology and drainage function.

scholarly journals RhoA- and Actin-Dependent Functions of Macrophages from the Rodent Cardiac Transplantation Model Perspective -Timing Is the Essence

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 70
Author(s):  
Malgorzata Kloc ◽  
Ahmed Uosef ◽  
Martha Villagran ◽  
Robert Zdanowski ◽  
Jacek Z. Kubiak ◽  
...  
Keyword(s):  
Immune Response ◽  
Circadian Rhythm ◽  
Immune Cells ◽  
Chronic Rejection ◽  
Cardiac Transplantation ◽  
Small Gtpase ◽  
Eukaryotic Cells ◽  
Transplantation Model

The small GTPase RhoA, and its down-stream effector ROCK kinase, and the interacting Rac1 and mTORC2 pathways, are the principal regulators of the actin cytoskeleton and actin-related functions in all eukaryotic cells, including the immune cells. As such, they also regulate the phenotypes and functions of macrophages in the immune response and beyond. Here, we review the results of our and other’s studies on the role of the actin and RhoA pathway in shaping the macrophage functions in general and macrophage immune response during the development of chronic (long term) rejection of allografts in the rodent cardiac transplantation model. We focus on the importance of timing of the macrophage functions in chronic rejection and how the circadian rhythm may affect the anti-chronic rejection therapies.

scholarly journals Lymphatics and Lymphangiogenesis in the Eye

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Shintaro Nakao ◽  
Ali Hafezi-Moghadam ◽  
Tatsuro Ishibashi
Keyword(s):  
Tumor Metastasis ◽  
Vision Loss ◽  
Transplant Rejection ◽  
Lymphatic Vessels ◽  
The Body ◽  
Corneal Transplant ◽  
Tissue Fluid ◽  
Ocular Diseases ◽  
Pathological Conditions

Lymphatic is a prerequisite for the maintenance of tissue fluid balance and immunity in the body. A body of evidence also shows that lymphangiogenesis plays important roles in the pathogenesis of diseases such as tumor metastasis and inflammation. The eye was thought to lack lymphatic vessels except for the conjunctiva; however, advances in the field, including the identification of lymphatic endothelial markers (e.g., LYVE-1 or podoplanin) and lymphangiogenic factors (e.g., VEGF-C), have revealed the exsitence and possible roles of lymphatics and lymphangiogenesis in the eye. Recent studies have shown that corneal limbus, ciliary body, lacrimal gland, orbital meninges, and extraocular muscles contain lymphatic vessels and that the choroid might have a lymphatic-like system. There is no known lymphatic outflow from the eye. However, several lymphatic channels including uveolymphatic pathway might serve the ocular fluid homeostasis. Furthermore, lymphangiogenesis plays important roles in pathological conditions in the eye including corneal transplant rejection and ocular tumor progression. Yet, the role of lymphangiogenesis in most eye diseases, especially inflammatory disease or edema, remains unknown. A better understanding of lymphatic and lymphangiogenesis in the eye will open new therapeutic opportunities to prevent vision loss in ocular diseases.

Abstract 17: Reverse Cholesterol Transport Relies on a Functional Lymphatic Network

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Catherine Martel ◽  
Andrew M Platt ◽  
Marit Westerterp ◽  
Robert Bittman ◽  
Allan R Tall ◽  
...  
Keyword(s):  
Flow Cytometric Analysis ◽  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Cholesterol Transport ◽  
Atherosclerotic Plaques ◽  
Flow Cytometric ◽  
Macrophage Cholesterol Efflux ◽  
Lymphatic Vasculature ◽  
Lymphatic Network

Introduction: HDL accepts free cholesterol from cells within extravascular tissues and transports it to the liver for excretion. Little is known about how HDL-C leaves such tissues to reach the blood. HDL-C is found in lymph, but it is unclear if lymphatics are critical for mobilization of HDL-C from tissues. Methods & Results: We employed models of disrupted lymphatic drainage--one a surgical resection of lymphatics in the mouse tail and the other a genetic lack of skin lymphatics due to a mutation in VEGFR3--to quantify the role of lymphatic vessels in movement of HDL-C out of skin to plasma. We implanted bone marrow macrophages loaded with [ 3 H]-cholesterol in skin sites and then quantified [ 3 H]-cholesterol in plasma, liver, and feces. [ 3 H]-cholesterol movement into plasma was reduced by 80% in both models of disrupted lymphatics, and this result was unaffected by conditions of a leaky blood vessels. To ensure that this reduction reflected events between efflux and appearance of cholesterol in plasma rather than altered macrophage cholesterol efflux, we substituted [ 3 H]-cholesterol-loaded macrophages with congenic macrophages loaded with a fluorescently modified cholesterol compound that allowed us to monitor ABCA1/ABCG1-dependent efflux from individual macrophages in the same assays and models. Flow cytometric analysis of bodipy-cholesterol-loaded macrophages retrieved from injection sites revealed similar efflux in mice lacking functional lymphatics as in controls. Conclusions: Mobilization of HDL-C from extravascular tissues to plasma occurs through the lymphatic vasculature. Recent studies show that transport through lymphatic vessels is compromised by hypercholesterolemia. Hypercholesterolemia-induced impairments in lymphatic function may retard clearance of cholesterol from extravascular tissues, possibly including atherosclerotic plaques.

The role of the graft endothelium in transplant rejection: Evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection

2000 ◽  
Vol 4 (4) ◽  
pp. 252-260 ◽  
Author(s):  
Mark D. Denton ◽  
Stacy F. Davis ◽  
Michelle A. Baum ◽  
Michael Melter ◽  
Marlies E. J. Reinders ◽  
...  
Keyword(s):  
Chronic Rejection ◽  
Transplant Rejection ◽  
Endothelial Activation ◽  
Clinical Marker

scholarly journals The Role of Lymphatic Marker Prox-1 in Relation to Brain Tumours

2021 ◽  
Vol 65 (4) ◽  
pp. 72-78
Author(s):  
J. Teleky ◽  
J. Király
Keyword(s):  
Brain Tumours ◽  
Current Knowledge ◽  
Treatment Options ◽  
Lymphatic Vessels ◽  
Homeobox Gene ◽  
Lymphatic Vasculature ◽  
Lymphatic Development ◽  
The Central Nervous System ◽  
The Brain

Abstract The homeobox gene, Prox-1 is a transcription factor essential for lymphatic development (lymphangiogenesis) during embryogenesis. It also performs different functions in various tissues such as: retina, lens, liver, pancreas and the central nervous system. Intense expression of Prox-1 has been demonstrated in the developing spinal cord and brain. In adulthood its expression continues in the hippocampus and cerebellum. In adult tissues the process of lymphatic vasculature formation is accompanied under certain pathological conditions such as inflammation, tissue repair and tumour growth. Prox-1 expression is typical for lymphatic vessels; thus it belongs to one of the most specific and widely used mammalian lymphatic endothelial marker in the detection of lymphangiogenesis and lymphatic vessel invasion in oncogenesis. It has been shown that Prox-1 is involved in cancer development and progression. It’s tumour suppressive and oncogenic properties are proven in several human cancers, including brain tumours. Among all body cancers the brain tumours represent the most feared tumours with very limited treatment options and a poor diagnosis. The aim of this paper was to show the current knowledge of the gene Prox-1 with an emphasis on brain tumours, especially in gliomas.

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