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LYMPHATIC STRUCTURE
AND FUNCTION IN HEALTH
AND DISEASE
LYMPHATIC STRUCTURE
AND FUNCTION IN HEALTH
AND DISEASE
Edited by
FELICITY N.E. GAVINS
Department of Life Sciences, Brunel University London,
Uxbridge, United Kingdom
J. STEVE ALEXANDER
Department of Molecular & Cellular Physiology, LSU Health Sciences Center,
Shreveport, LA, United States
Academic Press is an imprint of Elsevier
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Copyright © 2020 Elsevier Inc. All rights reserved.
Published in cooperation with The International Society for Neurovascular Disease.
No part of this publication may be reproduced or transmitted in any form or by any means,
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This book and the individual contributions contained in it are protected under copyright by the
Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical
treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described herein. In
using such information or methods they should be mindful of their own safety and the safety of
others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,
assume any liability for any injury and/or damage to persons or property as a matter of products
liability, negligence or otherwise, or from any use or operation of any methods, products,
instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
ISBN 978-0-12-815645-2
For information on all Academic Press publications visit our
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Publisher: Nikki Levy
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Cover Designer: Alan Studholme
Typeset by SPi Global, India
Dedication
This volume is dedicated to Dr. D. Neil Granger who has been our
steadfast friend and guiding mentor throughout our careers where
he had led the Department of Molecular and Cellular Physiology at
LSUHSC-Shreveport for over 30 years. As a leading pioneer in both
divisions of the blood and lymphatic vascular system, we would like
to recognize Dr. Granger and dedicate this edition to him.
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Contributors
J. Steve Alexander Department of Molecular and Cellular Physiology, LSU
Health Sciences Center, Shreveport, LA, United States
M. Amore Phlebology and Lymphology Unit, Cardiovascular Surgery Divi-
sion, Central Military Hospital; III Chair of Anatomy, Buenos Aires Univer-
sity, Buenos Aires, Argentina
Felix Becker Clinic of General, Visceral and Transplantation Surgery, Univer-
sity Hospital M
€
unster, M
€
unster, Germany
Anatoliy A. Gashev Department of Medical Physiology, College of Medicine,
Texas A&M University Health Science Center, Temple, TX, United States
Felicity N.E. Gavins Department of Molecular and Cellular Physiology, LSU
Health Sciences Center, Shreveport, LA, United States; Brunel University
London, Kingston Ln, London, Uxbridge, United Kingdom
B.B. Lee Vascular surgery, George Washington University Hospital,
Washington, DC, United States
Annika Mohr Clinic of General, Visceral and Transplantation Surgery, Uni-
versity Hospital M
€
unster, M
€
unster, Germany
Daniel Palmes Clinic of General, Visceral and Transplantation Surgery, Uni-
versity Hospital M
€
unster, M
€
unster, Germany
Matthew Stephens Department of Physiology & Pharmacology, Inflamma-
tion Research Network, Snyder Institute of Infection, Immunity & Inflamma-
tion, University of Calgary, Calgary, AB, Canada
H Suami Australian Lymphoedema Education, Research and Treatment,
Macquarie University, Sydney, Australia
Pierre-Yves von der Weid Department of Physiology & Pharmacology,
Inflammation Research Network, Snyder Institute of Infection, Immunity
& Inflammation, University of Calgary, Calgary, AB, Canada
J. Winny Yun Department of Molecular and Cellular Physiology, LSU Health
Sciences Center, Shreveport, LA, United States
David C. Zawieja Department of Medical Physiology, College of Medicine,
Texas A&M University Health Science Center, Temple, TX, United States
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About the Editors
Professor Felicity N.E. Gavins is
a pharmacologist whose research
interest focuses on developing antiin-
flammatory strategies that promote
resolution of inflammation following
ischemia reperfusion injury (I/RI) in
cardiovascular and cerebrovascular
diseases. She is specifically interested
in the role of the microvasculature
as a dynamic interface between
circulating blood and immune cells,
lymphatics, and tissue. Her group
studies how circulating cells commu-
nicate, adhere, and migrate across endothelial borders, along with
investigating how circulating and resident cells can render systemic
inflammatory responses and alter local inflammatory and throm-
botic states. More recently, Professor Gavins has expanded her
research to also cover microvascular dysfunction in the setting of
organ transplantation, as evidenced by enhanced solute barrier
function failure, neutrophil recruitment, and endothelial damage.
Professor J. Steve Alexander is a
cardiovascular biologist working on
how small blood vessels become
injured during the process of inflam-
mation. Several diseases including
stroke, cancer, Crohn’s disease, and
diabetes are associated with distur-
bances in how blood vessels restrict
exchange of their contents, leading
to the development of edema. His
current models indicate the dysregu-
lation of several classes of junctional
xiii
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molecules (tight or occludens junctions, adherens junctions, and
complexus adherens junctions) and mediate the elevated exchange
of solute proteins and inflammatory cells during active inflamma-
tion and in transplantation injury. A new and important direction
in this area of research is the development of models that consider
the lymphatic system and the growth of lymphatic endothelial cells
that is known to participate in not only tumor cell metastasis but also
acute and chronic inflammation.
xiv About the Editors
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CHAPTER
1
Introduction/overview
Felicity N.E. Gavins
a,b
, J. Steve Alexander
a
a
Department of Molecular and Cellular Physiology, LSU Health Sciences
Center, Shreveport, LA, United States
b
Brunel University London, Kingston Ln, London, Uxbridge,
United Kingdom
The lymphatic system consists of the vascular network of tissues
and organs (the lymph nodes, thymus, spleen, tonsils, and appen-
dix) that drain interstitial fluid (lymph) from the peripheral tissue
back to the blood circulation. The lymphatic system forms part of
the well-described vascular system but is not a circulatory system as
it is a group of one-way conduits. This incredibly complex network
of vessels not only collects lymph, which is an astounding feat at the
level of physics, but also plays a crucial role in our immune system;
it is the least well characterized and often maligned and marginal-
ized vascular system reflecting the great difficulty in visualizing
lymphatics outside of the confines of a fat-meal consumption, which
necessitated the identification of many molecular markers that dis-
tinguish lymphatic endothelial cells from the blood vascular endo-
thelium. Consequently, there has been more recently an explosion of
research into the lymphatic system with the annual number of pub-
lications on lymphatics climbing from 2093 in 1990 to 5519 in 2015.
The literature is proceeding so quickly that we thought that this area
of study deserved at this point a summary of how lymphatics and
lymphatic endothelial cells contribute to the functioning of several
different organ systems and to health and disease.
This text is therefore devoted to the evaluation of how the lym-
phatic organization and supply in several organ systems may con-
tribute to how these organs function and how their disturbances in
1Lymphatic Structure and Function in Health and Disease
https://doi.org/10.1016/B978-0-12-815645-2.00001-0
Copyright © 2020 Elsevier Inc. All rights reserved.
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structure, patterning, or function may lead to organ stress. The mul-
tifaceted roles that lymphatics play in health and disease include
contributions gathered from leading experts around the world
who are actively working in the rapidly expanding field of lym-
phatic research.
The lymphatic system was first described by Hippocrates of Kos
(c.460–377 BC), and as such, B.B. Lee and H. Suami have focused on
the evolution and the embryonic development of the lymphatic sys-
tem in Chapter 2. This team also brings together the recent advance
in the field of lymphangiogenesis, highlighting both the physiological
and pathological roles played by lymphatic development.
As mentioned earlier, the lymphatic system plays a key role in the
immune system. In Chapter 3, M. Stephens and Pierre-Yves von der
Weid focus on the role that lymphatic vessels and lymphatic con-
tractions play in edema resolution and immune cell trafficking,
especially in the context of the intestine and inflammatory processes
associated with the gastrointestinal tract. Stephens and von der
Weid discuss the implications and significance of lymph node swell-
ing (lymphadenopathy), which occurs in inflammation, infection, and
diseases. Finally, this chapter discusses the dysfunction of lym-
phatic vessel function in a variety of pathologies (often associated
with chronic inflammation) such as rheumatoid arthritis and osteo-
arthritis, elephantiasis, inflammatory bowel diseases, metabolic
syndrome and diabetes, and cancer, coupled with discussions
regarding the consequences of targeting lymphatic pump for thera-
peutic benefits.
Next, we move to the hydrodynamic regulation of lymphatic ves-
sel transport and the impact that aging has on these events
(Chapter 4). In this chapter, A.A. Gashev and D.C. Zawieja discuss
the concepts of intrinsic and extrinsic lymph pumps, along with
the job that they play in modulating lymphatic vessel contractility.
They will discuss the novel regulatory function of histamine as an
endothelium-derived relaxing factor (EDRF). Additionally, while
the important role that the aging process plays in and the impact it
has on the vascular system (termed vascular aging) are recognized,
very little is known with respect to lymphatic system and aging-
associated changes in the active lymph pumps. As such, A.A. Gashev
and D.C. Zawieja will discuss these issues in detail, bringing together
their own work and that of the scientific community.
2 1. Introduction/overview
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