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Inflammation
& Allergy - Drug Targets
(Formerly 'Current Drug Targets - Inflammation & Allergy')
ISSN: 1871-5281
Inflammation & Allergy
- Drug Targets
Volume 7, Number 3, September 2008
Contents
Potassium Channel Openers and Improvement of Toxic Stress:
Do they have Role in the Management of Inflammatory Bowel
Disease? Pp. 129-135
Azadeh Hosseini-Tabatabaei and Mohammad
Abdollahi
[Abstract]
The Role of Inflammation and Allergy in Acute
Coronary Syndromes Pp. 136-144
Beste Ozben and Okan Erdogan
[Abstract]
Metal Allergens of Growing Significance:
Epidemiology, Immunotoxicology, Strategies for Testing and
Prevention Pp. 145-162
Giovanni Forte, Francesco Petrucci and
Beatrice Bocca
[Abstract]
Proteomic Screening Points to the Potential
Importance of Ara h 3 Basic Subunit in Allergenicity of Peanut
Pp. 163-166
Baozhu Guo, Xianquiang Liang, Si-Yin Chung
and Soheila J. Maleki
[Abstract]
Effects of Sublingual Immunotherapy on
Allergic Inflammation Pp. 167-172
Cristoforo Incorvaia, Franco Frati, Paola
Puccinelli, Francesco Marcucci, Giuseppe Di Cara, Laura Sensi,
Silvia Scurati, Mona-Rita Yacoub and Philippe Moingeo
[Abstract]
Non-IgE Mediated Food Allergy Pp.
173-180
Harumi Jyonouchi
[Abstract]
Innovative Therapeutic Strategies for
Restoring Lymphocyte Functions in Septic Patients Pp.
181-186
Fanny Turrel, Caroline Guignant, Fabienne
Venet, Alain Lepape and
Guillaume Monneret
[Abstract]
Cytokines in Colitis Associated Cancer:
Potential Drug Targets? Pp. 187-194
Maximilian J. Waldner and Markus
F. Neurath
[Abstract]
Lead Compounds for Anti-inflammatory Drugs Isolated
from the Plants of the Traditional Oriental Medicine in Korea
Pp. 195-202
JangJa Hong, Kuk Hyun Shin, Soon Sung Lim,
Jong Hwan Kwak, OkPyo Zee, Kenji Ishihara, Noriyasu Hirasawa,
Toshio Seyama and Kazuo Ohuchi
[Abstract]
Therapeutic Benefits of Regulating Inflammation
in Autoimmunity Pp. 203-210
Enayat Nikoopour, Jordan Ari Schwartz and Bhagirath
Singh
[Abstract]
Abstracts
[Back to top]
Potassium Channel Openers and Improvement of Toxic Stress:
Do they have Role in the Management of Inflammatory Bowel
Disease?
Azadeh Hosseini-Tabatabaei and Mohammad
Abdollahi
Inflammatory bowel disease (IBD) is a progressive condition
in gastrointestinal tract, which refers to two idiopathic
diseases; ulcerative colitis and Crohn's disease. Although
certain etiology of these conditions is not known, it seems
that an abnormality in reaction and regulation of the immune
system plays an important role in adventure of the disease.
According to the investigations, it is likely that oxidative
and nitrosative stress have etiologic roles in IBD. Their
destructive effects may contribute to the initiation or progression
of the disease. Nowadays, the effectiveness of different medicines
in the treatment of IBD has been proved, but none of them
has shown a desirable result. Potassium channel openers (PCOs)
are a class of drugs with various usages in the aspects of
cardiovascular diseases and urinary incontinence. Their major
mechanism is the opening of ATP-sensitive potassium (K-ATP)
channels and contribute to the relaxation of smooth muscles.
Nicorandil is a member of PCOs, with a special chemical structure.
Recent investigations mention some novel effects and functions
for this drug. Nicorandil reveals an anti-apoptosis property
not only via a nitric oxide (NO)/cGMP-dependent mechanism,
but also through activating mitochondrial K-ATP channels.
Nicorandil can also elevate cGMP levels in some tissues, without
direct NO generation. Gastroprotective activity via opening
of the K channels, free radical scavenging, prostaglandin
E2 elevation, decreasing pepsin and acid secretion, and prevention
of the detrimental rise in NO has been proposed for nicorandil.
According to these protective mechanisms and the role of oxidative/nitrosative
stress in the expression of IBD, we herein hypothesize that
nicorandil and other PCOs with similar structure can be used
in the management of IBD. This approach offers new hope for
the successful treatment of IBD. Further investigations on
animal models are needed, to place nicorandil and similar
drugs alongside IBD therapy.
[Back to top]
The Role of Inflammation and Allergy in Acute
Coronary Syndromes
Beste Ozben and Okan Erdogan
It is well known that inflammatory mechanisms play a
crucial role in the pathogenesis of atherosclerosis and coronary
artery disease. In recent years, allergic episodes have been
shown to be associated with acute coronary syndromes. Mast
cells release certain inflammatory mediators including histamine
and neutral proteases during an allergic episode and these
inflammatory mediators are implied to induce coronary artery
spasm and/or atheromatous plaque erosion or rupture. As the
inflammatory component of acute coronary syndromes is a potential
therapeutic target, drugs that stabilize mast cell membrane
and monoclonal antibodies that protect mast cell surface may
be effective in preventing allergy associated acute coronary
syndromes. In this review, we will mention the role of inflammation
and allergy and anti-inflammatory therapeutic modalities in
acute coronary syndromes.
[Back to top]
Metal Allergens of Growing Significance: Epidemiology, Immunotoxicology,
Strategies for Testing and Prevention
Giovanni Forte, Francesco Petrucci and
Beatrice Bocca
Metal-induced allergic contact dermatitis (ACD) is expressed
in a wide range of cutaneous reactions following dermal and
systemic exposure to products such as cosmetics and tattoos,
detergents, jewellery and piercing, leather tanning, articular
prostheses and dental implants. Apart from the well known
significance of nickel in developing ACD, other metals such
as aluminium, beryllium, chromium, cobalt, copper, gold, iridium,
mercury, palladium, platinum, rhodium and titanium represented
emerging causes of skin hypersensitivity. Despite the European
Union directives that limit the total nickel content in jewellery
alloys, the water soluble chromium (VI) in cement, and metals
banned in cosmetics, the diffusion of metal-induced ACD remained
quite high. On this basis, a review on the epidemiology of
metal allergens, the types of exposure, the skin penetration,
the immune response, and the protein interaction is motivated.
Moreover, in vivo and in vitro tests for
the identification and potency of skin-sensitizing metals
are here reviewed in a risk assessment framework for the protection
of consumer’s health. Avenues for ACD prevention and
therapy such as observance of maximum allowable metal levels,
optimization of metallurgic characteristics, efficacy of chelating
agents and personal protection are also discussed.
[Back to top]
Proteomic Screening Points to the Potential Importance of
Ara h 3 Basic Subunit in Allergenicity of Peanut
Baozhu Guo, Xianquiang Liang, Si-Yin Chung
and Soheila J. Maleki
Peanuts are complex storage proteins with high contents
and have been identified as one of the most allergenic foods.
In this review, we summarize some of the latest findings and
the potential importance of the Ara h 3 basic subunit, which
has been overlooked as an allergen in early literature. Some
recent studies indicate that Ara h 3 basic subunit may be
as significant as or even a more important allergen than the
acidic subunit. For example, one clinical study found a group
of children with peanut allergy who were specifically sensitized
to the basic subunit of Ara h 3. Although, proteomic analysis
of total peanut storage proteins has revealed limited polymorphic
profiles of major proteins in diverse peanut germplasm accessions,
a study reported a peanut breeding line ‘GT-C9’
lacking several seed protein peptides, in which the missed
major proteins were basic subunits of Ara h 3. This breeding
line was shown to exhibit significantly lower levels of advanced
glycation end (AGE) products and IgE binding by the sera of
peanut allergic patients, which implies a role for the basic
subunit of Ara h 3 in the allergenicity of peanuts. Further
studies are needed to investigate the contribution of Ara
h 3 basic subunits to peanut allergenicity.
[Back to top]
Effects of Sublingual Immunotherapy on Allergic Inflammation
Cristoforo Incorvaia, Franco Frati, Paola
Puccinelli, Francesco Marcucci, Giuseppe Di Cara, Laura Sensi,
Silvia Scurati, Mona-Rita Yacoub and Philippe Moingeo
The clinical expression of the most common allergic
diseases reflects allergic inflammation and underlines that
inflammation is the main target of anti-allergic therapies.
Allergen specific immunotherapy (AIT) has a recognized impact
on allergic inflammation, which persists after its discontinuation,
and is the only therapy able to modify the natural history
of allergic march. The traditional, subcutaneous route of
administration is effective in altering the phenotype of allergen-specific
T cells, switching from a Th2-type response, characterized
by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines
to a Th1–type response. This immune deviation is related
to an increased IFN-gamma and IL-2 production as well as to
the anergy or tolerance of Th2, the latter related to the
generation of allergen-specific T regulatory (Treg) cells,
which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory
mechanisms observed during sublingual IT with high allergen
doses proved to be similar compared to subcutaneous immunotherapy.
Recent data obtained in biopsies clearly indicate that the
pathophysiology of the oral mucosa, and in particular mucosal
dendritic cells, plays a pivotal role in inducing tolerance
to the administered allergen.
[Back to top]
Non-IgE Mediated Food Allergy
Harumi Jyonouchi
Adverse reactions to dietary proteins (DPs) can impose
a significant impact on one’s daily life and can even
affect the ‘life style’ of an entire family. Adverse
reactions to DPs may or may not be immune-mediated. The immune-mediated
adverse reaction to food is defined as food allergy (FA) which
is roughly divided into IgE mediated or non-IgE mediated FA
(NFA). As opposed to IgE mediated FA, NFA primarily affects
the GI mucosa. In addition, there is far less of an understanding
of NFA than IgE-mediated FA and its clinical relevance is
likely under-estimated in most cases. This is partly due to
delayed onset of symptoms and subsequent difficulty in making
the clinical association between offending food and clinical
symptoms. The lack of easily accessible diagnostic measures
also contributes to the problem.
The gut mucosal barrier is thought to have developed to execute
an immensely difficult task; digestion and absorption of nutrients
without provoking immune responses and cohabiting with commensal
flora in a mutual beneficial relationship, while maintaining
an immune defense against pathogenic microbes. The gut mucosal
immune system accomplishes this task partly by establishing
tolerance to macronutrients with potent immunogenecity. Immune
tolerance to macronutrients (DPs) is maintained in part by
active suppressive mechanisms involving antigen (Ag)-specific
regulatory T (Treg) cells. This active immune tolerance state
appears to be affected by various environmental factors such
as change in commensal flora.
In the first few years of life, humans gradually develop an
intricate balance between tolerance and immune reactivity
in the gut mucosa along with a tremendous expansion of gut
associated lymphoid tissue (GALT). Not surprisingly, both
IgE and non-IgE mediated food allergy (FA) is frequently seen
during this period. The most common causative DPs for NFA
are those contained in infant formulas (cow’s milk and
soy proteins). Unlike IgE mediated FA, NFA is rarely life-threatening.
However, NFA to DPs can cause significant morbidity in rapidly
growing infants and young children. A better understanding
of pathogenesis of NFA is crucial for timely management of
NFA in this vulnerable population.
This review discusses the gut mucosal immune system in the
first few years of life including genetic/environmental factors
affecting the development of mucosal immune system and pathogenesis
of NFA in association with clinical/laboratory findings.
[Back to top]
Innovative Therapeutic Strategies for Restoring Lymphocyte
Functions in Septic Patients
Fanny Turrel, Caroline Guignant, Fabienne
Venet, Alain Lepape and Guillaume Monneret
Septic syndromes still remain a major but largely under-recognized
healthcare problem worldwide accounting for thousands of deaths
every year. Despite numerous clinical trials, therapies have
failed to mitigate the devastating effects of these conditions.
It is now agreed that the initial hypotheses for sepsis pathophysiology
have been misconstrued. Sepsis deeply perturbs immune homeostasis
by concomitantly inducing a strong inflammatory response and
a major anti-inflammatory process, acting as a negative feedback.
Several lines of evidences indicate that this inhibitory response
secondly may be deleterious in patients who survived initial
resuscitation, as it may be directly responsible for worsening
outcome by decreasing resistance to secondary nosocomial infections.
In this context, while the majority of clinical and basic
science conducted so far has focused on innate immune cell
depressed functions (especially monocytes), the contribution
of T lymphocyte anergy has been somewhat ignored. This review
focuses on lymphocyte dysfunctions described so far in patients
and on potential new therapeutic strategies aimed at restoring
a functional lymphocytic response after sepsis.
[Back to top]
Cytokines in Colitis Associated Cancer: Potential Drug Targets?
Maximilian J. Waldner and Markus
F. Neurath
In inflammatory bowel disease (IBD), such as UC and CD, the
development of colorectal carcinoma can be initiated through
chronic inflammation, depending on the duration and severity
of the disease. Growing evidence supports a role for various
cytokines, released by epithelial and immune cells, in the
pathogenesis of colitis associated cancer (CAC).
For instance, TNF α
has been recently shown to promote tumor development in experimental
colitis. Due to its role in the pathogenesis of IBD, TNF-α
blockade has become one of the cornerstones of IBD therapy.
Thus, anti TNF-α
strategies could also provide effective anti tumor therapies.
TGF-β
has been shown to attenuate an anti tumor immune response
through the induction of regulatory T cells in spontaneous
and inflammation associated cancer. However, IL 6 signaling
promotes tumor growth in experimental CAC, and this signaling
is inhibited by TGF-β.
Members of the IL 12 family, such as IL 12, IL 23, and IL
27, have been implicated in pathogenesis of colitis and IL
23 seems to be involved in inflammation associated carcinogenesis.
However, a role for those cytokines in CAC remains to be shown.
Whereas the above-mentioned cytokines promote tumor growth,
others provide an anti tumor effect. IL 10 deficient mice
develop colitis and CAC a few weeks after birth. Besides its
immunosuppressive properties, IL 10 also has anti angiogenic
and both tumor promoting and –inhibiting properties,
which could be responsible for these observations.
Since most of the above mentioned cytokines are involved in
both, inflammation and carcinogenesis, it is difficult to
account their contribution to the individual steps during
pathogenesis of CAC. However, as already shown in IBD, cytokines
may also provide promising therapeutic targets in CAC.
[Back to top]
Lead Compounds for Anti-inflammatory Drugs Isolated
from the Plants of the Traditional Oriental Medicine in Korea
JangJa Hong, Kuk Hyun Shin, Soon Sung Lim,
Jong Hwan Kwak, OkPyo Zee, Kenji Ishihara, Noriyasu Hirasawa,
Toshio Seyama and Kazuo Ohuchi
Effects of compounds isolated from medicinal plants in Korea
on prostaglandin E2 (PGE2)
production in rat peritoneal macrophages were examined, and
mechanism of action of the active constituents was analyzed.
The active constituents were as follows; tectorigenin and
tectoridin isolated from the rhizomes of Belamcanda chinensis,
platycodin D isolated from the roots of Platycodon grandiflorum,
imperatorin isolated from the roots of Angelica dahurica,
and hyperin isolated from the roots of Acanthopanax chiisanensis.
These compounds inhibit the induction of cyclooxygenase-2
(COX-2), thus inhibiting PGE2
production. The chemically synthesized chalcone derivative,
2’-hydroxy-4’-methoxychalcone, also inhibits PGE2
production by suppressing COX-2 induction. In contrast, taiwanin
C isolated from the roots of Acanthopanax chiisanensis
inhibited PGE2 production
by direct inhibition of COX-1 and COX-2.
[Back to top]
Therapeutic Benefits of Regulating Inflammation in Autoimmunity
Enayat Nikoopour, Jordan Ari Schwartz and
Bhagirath Singh
Autoimmunity results from the dysregulation of the immune
system leading to tissue damage. Th1 and Th17 cells are known
to be cellular mediators of inflammation in autoimmune diseases.
The specific cytokine milieu within the site of inflammation
or within secondary lymphatic tissues is important during
the priming and effector phases of T cell response. In this
review, we will address the nature of the inflammatory response
in the context of autoimmune disease, specifically we will
discuss the role of dendritic cells following stimulation
of their innate pathogen recognition receptors in directing
the development of T cell responses. We will focus on how
dendritic cell subsets change the balance between major players
in autoimmunity, namely Th1, Th17 and regulatory T cells.
Th17 cells, once thought to only act as pathogenic effectors
through production of IL-17, have been shown to have regulatory
properties as well with coproduction of the anti-inflammatory
cytokine IL-10 by a subset now referred to as regulatory Th17
cells. IL-17 is important in the induction of autoimmune diseases
such as experimental autoimmune encephalomyelitis (EAE) and
inflammatory bowel disease (IBD). Study of the inflammatory
process following encounter with agents that stimulate the
innate immune responses such as adjuvants opens a new horizon
for the discovery of therapeutic agents including those derived
from microorganisms. Microbial products such as adjuvants
that function as TLR ligands may stimulate the immune system
by interacting with Toll-like receptors (TLR) on antigen-presenting
cells. Microbial agents such as Bacille Calmette-Guérin
(BCG) or Freund's adjuvant (CFA) that induce a Th17 response
are protective in models of autoimmune diseases particularly
EAE and type 1 diabetes (T1D). The induction of innate immunity
by these microbial products alters the balance in the cytokine
microenvironment and may be responsible for modulation of
the inflammation and protection from autoimmunity.
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