Endocrine,
Metabolic & Immune Disorders - Drug Targets
ISSN: 1871-5303
Endocrine, Metabolic &
Immune Disorders - Drug Targets
Volume 10, Number 4, December 2010
Contents
Tissue Fibrosis
Guest Editor: Shizuya Saika
Editorial: Pp.
301
Integrins Modulate Cellular Fibrogenesis at Multiple Levels:
Regulation of TGF-β
Signaling Pp. 302-319
Tomoko Hayashida
[Abstract] [Purchase
Article] [PMID:
20925652 PubMed - indexed for MEDLINE]
Wound-Associated Skin Fibrosis: Mechanisms and
Treatments Based on Modulating the Inflammatory Response
Pp. 320-330
Tanya J. Shaw, Kazuo Kishi and Ryoichi Mori
[Abstract] [Purchase
Article] [PMID:
20923404 PubMed - indexed for MEDLINE]
Fibrosis in the Anterior Segments of the Eye Pp.
331-335
Osamu Yamanaka, Chia-Yang Liu and Winston
W.-Y. Kao
[Abstract] [Purchase
Article] [PMID:
20925651 PubMed - indexed for MEDLINE]
General Articles
The Leptin System: A Potential Target for Sepsis Induced
Immune Suppression Pp. 336-347
Johannes Tschöp, Jonathan R. Dattilo, Priya S. Prakash,
Kevin R. Kasten, Matthias H. Tschöp and Charles C. Caldwell
[Abstract]
[Purchase
Article] [PMID:
20923403 PubMed - indexed for MEDLINE]
Isoforms of Vitamin E Differentially Regulate Inflammation
Pp. 348-366
Joan M. Cook-Mills and Christine A.
McCary
[Abstract]
[Full
Text Article] [PMID:
20923401 PubMed - indexed for MEDLINE]
PKC-Ø
is A Drug Target for Prevention of T Cell-Mediated Autoimmunity
and Allograft Rejection Pp. 367-372
Myung-Ja Kwon, Ruiqing Wang, Jian Ma and
Zuoming Sun
[Abstract] [Purchase
Article][PMID:
20923402 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
EDITORIAL: Tissue Fibrosis
Wound healing process may lead to undesirable outcome, tissue
fibrosis or scarring, and affect the organ function in various
organs. Body surface, i. e., skin, mucosa including ocular
surface, directly receive external stimuli, and injured.Excess
scarring in such tissues is to be prevented to maintain their
function or an outward appearance of a patient. Surface epithelium
and underlying mesenchymal cells, as well as inflammatory
cells, are involved in the wound healing in these tissues.
Well-organized cell behaviors are essential to the restoration
of normal function of the skin or ocular surface. In this
mini-hot topic issue, we have three articles focusing on wound
healing and fibrosis in skin and ocular surface, as well as
the role of epithelial integrin on wound healing-related cytokine
signaling. Understanding the mechanism of wound healing of
such organs is essential to develop new prevention strategies
of undesirable fibrosis or scarring.
Shizuya Saika, MD, PhD
(Guest Editor)
Dept. of Ophthalmology
Wakayama Medical University
811-1 Kimiiidera, Wakayama,
641-0012, Japan
Tel: 81-73-447-2300 (5412, 5410)
Fax: 81-73-448-1991
E-mail: shizuya@wakayama-med.ac.jp
[Back to top] [Purchase
Article] [PMID:
20925652 PubMed - indexed for MEDLINE]
Integrins Modulate Cellular Fibrogenesis at Multiple
Levels: Regulation of TGF-β
Signaling
Tomoko Hayashida
Fibrosis could occur in virtually any organ or tissue. The
fibrotic lesion indolently disrupts the structure of the healthy
organ, thereby hampering its proper function, consequence
of which is devastating. Among the myriad factors that modulate
fibrogenesis, transforming growth factor β
(TGF-β)
is one of the most studied and its central role for fibrotic
disorders has been strongly suggested. Due to the pleiotropic
nature of this cytokine, TGF-β
modulates multiple cellular responses throughout fibrogenesis.
The complexity is supported by the TGF-β
receptor-specific phosphorylation of both the canonical, Smad-,
and non-canonical, “non-Smad,” pathways. The latter
modulates Smad activity either independent of Smad or by phosphorylating
the Smad linker region, distinct from those receptor-regulated.
Despite the commodity of this mediator, the mechanism by which
TGF-β
signaling causes specific pathogenesis and disease varies
depending on the nature of the organ and the cells that compose
that organ. Cells express a specific series of integrins that
act as cellular sensors for the extracellular environment,
determining subsequent cellular signals in a cell-type specific
manner. Integrins may change their expression pattern under
pathological conditions and contribute to the regulation of
fibrogenesis via modulating ambient TGF-β
activity. This regulation includes release of active TGF-β
from its latent form and modulation of various signals downstream
of integrin-engagement, which participate in the non-canonical
regulation of TGF-β
signaling. TGF-β
also induces expression of integrins, as well as their ligand
extracellular matrix, generating an amplification loop. Furthermore,
myriads of intracellular signaling molecules that associate
with integrin engagement could non-canonically modulate TGF-β
signals. The entire picture of this mutual regulation between
integrin and the TGF-β
pathways might be difficult to draw. Instead, this review
intends to depict several critical aspects of this regulation,
with examples from various types of fibrosis in different
tissues to help understand the integrin-modulation of fibrogenesis,
a critical clue for therapeutic approaches to fibrosis.
[Back to top]
[Purchase Article] [PMID:
20923404 PubMed - indexed for MEDLINE]
Wound-Associated Skin Fibrosis: Mechanisms and Treatments
Based on Modulating the Inflammatory Response
Tanya J. Shaw, Kazuo Kishi and Ryoichi Mori
Skin fibrosis, in its mildest form, may present only a minor
aesthetic problem, but in the most severe cases it can lead
to debilitating pathologies of the skin, for example keloid
and hypertrophic scars, and systemic sclerosis. In recent
years, extensive basic research aimed at understanding the
molecular mechanisms underlying fibrosis has revealed an impressive
but baffling number of genes, molecules, and cell types that
may contribute to this problem. However, one recurring and
consistent theme in these studies is that inflammatory cells
and their secreted mediators appear to be leading culprits
in activating dermal fibroblasts to become fibrotic. This
review will first describe the histology of normal versus
fibrotic skin, and will also describe the process of wound
repair, a primary cause of skin fibrosis. We will then focus
on what is currently known about the molecular mechanisms
underlying skin fibrosis, with particular attention paid to
how inflammation contributes. Finally, current treatment strategies
and emerging therapeutic targets will be discussed.
[Back to top] [Purchase
Article] [PMID:
20925651 PubMed - indexed for MEDLINE]
Fibrosis in the Anterior Segments of the Eye
Osamu Yamanaka, Chia-Yang Liu and Winston
W.-Y. Kao
The anterior segment of the eye ball, i. e., cornea and conjunctiva,
serves as the barrier to the external stimuli. Cornea is transparent
and is a “window” of the light sense, while conjunctiva
covers the sclera, the main part of the eyeshell. Fibrosis/scarring
in cornea potentially impairs vision by the reduction of its
transparency and the alteration of the regular curvature.
Fibrotic reaction in conjunctiva is also of clinical importance
because inflammatory fibrosis in this tissue affects the physiology
of the cornea and also a problem of post-eye surgery. In this
review, we discuss the topic that is quite critical in vision.
Although, various growth factors have been considered to be
involved in, focus was put on the roles of transforming growth
factorβ
(TGFβ).
[Back to top] [Purchase
Article] [PMID:
20923403 PubMed - indexed for MEDLINE]
The Leptin System: A Potential Target for Sepsis Induced Immune
Suppression
Johannes Tschöp, Jonathan R. Dattilo, Priya S. Prakash,
Kevin R. Kasten, Matthias H. Tschöp and Charles C. Caldwell
Sepsis, which is defined as a systemic inflammatory response
syndrome that occurs during infection, is associated with
several clinical conditions and high mortality rates. As sepsis
progresses immune paralysis can become severe, leaving an
already vulnerable patient ill equipped to eradicate primary
or secondary infections. At present the predominant treatments
for sepsis have not demonstrated convincing efficacy of decreased
mortality. During sepsis, it has been observed that leptin
levels initially increase but subsequently decline. A body
of evidence has demonstrated that central or systemic leptin
can beneficially regulate immune function. In this report
expression of leptin and its receptor, signaling, and function
on leukocytes will be reviewed. Furthermore, the effects mediated
by central and systemic leptin during sepsis will be reviewed.
Altogether, the ability of leptin to beneficially enhance
inflammation and the host response during sepsis supports
its use as a therapeutic agent, particularly during the latter
phases of the syndrome.
[Back to top] [Full
Text Article] [PMID:
20923401 PubMed - indexed for MEDLINE]
Isoforms of Vitamin E Differentially Regulate Inflammation
Joan M. Cook-Mills and Christine A.
McCary
Vitamin E regulation of disease has been extensively studied
in humans, animal models and cell systems. Most of these studies
focus on the α-tocopherol
isoform of vitamin E. These reports indicate contradictory
outcomes for anti-inflammatory functions of the α
-tocopherol isoform of vitamin E, especially with regards
to clinical studies of asthma and atherosclerosis. These seemingly
disparate clinical results are consistent with recently reported
unrecognized properties of isoforms of vitamin E. Recently,
it has been reported that physiological levels of purified
natural forms of vitamin E have opposing regulatory functions
during inflammation. These opposing regulatory functions by
physiological levels of vitamin E isoforms impact interpretations
of previous studies on vitamin E. Moreover, additional recent
studies also indicate that the effects of vitamin E isoforms
on inflammation are only partially reversible using physiological
levels of a vitamin E isoform with opposing immunoregulatory
function. Thus, this further influences interpretations of
previous studies with vitamin E in which there was inflammation
and substantial vitamin E isoforms present before the initiation
of the study. In summary, this review will discuss regulation
of inflammation by vitamin E, including alternative interpretations
of previous studies in the literature with regards to vitamin
E isoforms.
[Back to top] [Purchase
Article] [PMID:
20923402 PubMed - indexed for MEDLINE]
PKC-Ø
is A Drug Target for Prevention of T Cell-Mediated Autoimmunity
and Allograft Rejection
Myung-Ja Kwon, Ruiqing Wang, Jian Ma and
Zuoming Sun
Protein kinase C theta (PKC-Ø)
is a key kinase in mediating T cell receptor (TCR) signals.
PKC-Ø
activated by T cell receptor (TCR) engagement translocates
to immunological synapses and regulates the activation of
transcriptional factors NF-κB,
AP-1, and NFAT. These transcription factors then activate
target genes such as IL-2. T cells deficient in PKC-Ø
display defects in T cell activation, survival, activation-induced
cell death, and the differentiation into inflammatory T cells,
both in vitro and in vivo. Since these effector
T helper cells are responsible for mediating autoimmunity,
selective inhibition of PKC-Ø
is considered a treatment for prevention of autoimmune diseases
and allograft rejection.
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