Lactoferrin and its Role in Wound Healing

120 Pages·2011·3.291 MB·English

by  Yoshiharu Takayama

Lactoferrin and its Role in Wound Healing

Yoshiharu Takayama
Lactoferrin and its Role
in Wound Healing
Yoshiharu Takayama
Functional Bio-molecules
Research Team
National Institute of Livestock
and Grassland Science
Ikenodai 2
305-0901 Tsukuba, Ibaraki
Japan
[email protected]
ISBN 978-94-007-2466-2 e-ISBN 978-94-007-2467-9
DOI 10.1007/978-94-007-2467-9
Springer Dordrecht Heidelberg London New York
Library of Congress Control Number: 2011939477
© Springer Science+Business Media B.V. 2012
No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any
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Printed on acid-free paper
Springer is part of Springer Science+Business Media (www.springer.com)
I dedicate this book to my father, Noboru
Takayama, who passed away during the
writing of this book.

Preface
Lactoferrin (lactotransferrin) was fi rst identifi ed as an iron-binding protein abundantly
found in milk. It is synthesized by glandular epithelial cells and secreted into body
fl uids such as saliva, tears and mucosal secretions. Lactoferrin has been considered to
play important roles in host defense, since lactoferrin shows broad spectrum of anti-
bacterial and anti-viral activities, arising from its iron-chelating property. However,
some functions of lactoferrin are independent from its iron chelating ability.
In addition, lactoferrin is known as a major component of secondary granules of
neutrophils. Plasma lactoferrin concentration is dramatically increased by bacterial
infection or tissue injury. Lactoferrin can regulate the function of innate and adaptive
immune cells and exhibits immunoregulation activity.
One of the most novel activity described for lactoferrin is its regulatory function
in wound healing. The results of animal studies indicate that the topical administration
of lactoferrin enhances the rate of skin wound closure in control and diabetic mice.
Skin wound healing is a complex physiological process that requires the regulation
of different types of cells such as immune cells, keratinocytes, fi broblasts, and endo-
thelial cells. Infl ammation is prerequisite for wound healing. The promoting effect
of lactoferrin on wound closure is likely to dependent on its immune regulatory
function. In addition, the results of recent in vitro and in vivo studies show that lac-
toferrin is a potent regulator of dermal fi broblasts and epidermal keratinocytes, and
promotes skin or corneal epithelial wound healing by increasing their proliferation,
migration or deposition of extracellular matrix (ECM) components such as collagen
and hyaluronan. Hyaluronan (hyaluronic acid) is a glycosaminoglycan distributed
throughout connective and epithelial tissues. The role of hyaluronan in wound heal-
ing is the promotion of cell proliferation and motility.
The aim of this book is to describe how lactoferrin directly or indirectly regulates
the wound healing processes that consists of multiple steps. Lactoferrin exerts its
biological effects by binding to specifi c lactoferrin receptors on target cells. The diverse
functions result from activation of different receptors and signal transduction path-
ways, and also from differences in the expression levels of receptors. This book will
describe an overview of molecular basis of wound healing (Chap. 1 ), in addition to
providing a general review of hyaluronan (Chap. 2 ) and lactoferrin (Chap. 3 ) and
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viii Preface
role of lactoferrin as signaling mediator (Chap. 4 ). Finally, the effects of lactoferrin
on wound healing are summarized in Chap. 5 .
The multi-functionality of lactoferrin fosters usage of lactoferrin as a therapeutic
agent for non-healing chronic wounds. A special feature of chronic wound is
prolonged or excessive infl ammatory response at the wounded site. Current therapy
using recombinant growth factor is partially effective for healing of chronic wounds.
In the clinical trial of patients with diabetic foot ulcers, the group treated with human
recombinant lactoferrin showed signifi cant improvement of wound healing rates
compared with placebo group. Based on these fi ndings, lactoferrin should be used
in patients with diabetic and other types of ulcers.
Yoshiharu Takayama
Contents
1 Molecular Regulation of Skin Wound Healing ...................................... 1
1.1 Introduction ...................................................................................... 1
1.2 Immediate Response ........................................................................ 2
1.3 Infl ammatory Response ................................................................... 3
1.4 Reepithelialization ........................................................................... 5
1.5 Granulation Tissue Formation.......................................................... 8
1.6 Wound Contraction .......................................................................... 8
1.7 Angiogenesis .................................................................................... 10
1.8 Remodeling ...................................................................................... 11
1.9 Resolution of Infl ammation ............................................................. 11
1.10 Proteases in Wound Healing ............................................................ 12
1.11 Anti-microbial Peptides ................................................................... 14
1.12 Chronic Wound Healing................................................................... 14
References ................................................................................................... 15
2 Role of Hyaluronan in Wound Healing ................................................... 25
2.1 Structure ........................................................................................... 25
2.2 Biosynthesis ..................................................................................... 26
2.3 Hyaluronan Receptor ....................................................................... 27
2.4 Mammalian Hyaluronidase .............................................................. 29
2.5 Hyaluronan Fragment ...................................................................... 30
2.6 Role on Cancer ................................................................................. 31
2.7 Hyaluronan in Dermis and Epidermis .............................................. 31
2.8 Role on Wound Healing ................................................................... 32
References ................................................................................................... 35
3 Lactoferrin Structure Function and Genetics ........................................ 43
3.1 Introduction ...................................................................................... 43
3.2 Lactoferrin Expression and Localization ......................................... 44
3.3 Lactoferrin Structure ........................................................................ 44
3.4 Iron-Binding Properties of Lactoferrin ............................................ 47
3.5 Lactoferrin Metabolism ................................................................... 47
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