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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 6, June 2006
Contents
Molecular Targets in Chronic Obstructive Airway Diseases
Guest Editors: David A. Groneberg and Tobias Welte
Editorial Pp.
639-641
Nanoparticle-Based Diagnosis and Therapy Pp.
643-648
D.A. Groneberg, M. Giersig, T. Welte and U. Pison
[Abstract]
New Insights into the Molecular Mechanisms of Corticosteroids
Actions Pp. 649-660
I.M. Adcock, G. Caramori and K. Ito
[Abstract]
Nuclear Factor Kappa B is a Promising Therapeutic Target in
Inflammatory Lung Disease Pp.
661-668
G.Y. Park and J.W. Christman
[Abstract]
Chemokine Receptors in Chronic Obstructive Pulmonary
Disease (COPD) Pp. 669-674
P. Panina, M. Mariani and D. D’Ambrosio
[Abstract]
Cytokines as Targets in Chronic Obstructive Pulmonary
Disease Pp. 675-681
K.F. Chung
[Abstract]
Targeting Transcription: A New Concept of Anti-Inflammatory
Therapy of Airway Diseases Pp. 683-689
D. Quarcoo and E. Hamelmann
[Abstract]
Targeting Mitogen-Activated Protein Kinases for Asthma Pp.
691-698
W. Duan and W.S.F. Wong
[Abstract]
Adenosine Receptors As Promising Therapeutic Targets
for Drug Development in Chronic Airway Inflammation Pp.
699-706
R. Polosa and S.T. Holgate
[Abstract]
Antioxidant Therapeutic Targets in COPD Pp.
707-720
I. Rahman and I. Kilty
[Abstract]
Nitric Oxide Synthase (NOS) as Therapeutic Target
for Asthma and Chronic Obstructive Pulmonary Disease
Pp.721-735
F.L.M. Ricciardolo, F.P. Nijkamp and G. Folkerts
[Abstract]
The Vasculature as a Target in the Treatment of Pulmonary
Emphysema Pp. 737-741
H.A. Golpon and N.F. Voelkel
[Abstract]
Antimicrobial Peptides in COPD - Basic Biology and
Therapeutic Applications Pp. 743-750
R. Bals and P.S. Hiemstra
[Abstract]
Proteases and Their Role in Chronic Inflammatory Lung
Diseases Pp. 751-759
F. Bühling, D. Groneberg and T. Welte
[Abstract]
General Articles
Leptin: A Promising Therapeutic Target with
Pleiotropic Action Besides Body Weight Regulation Pp.
761-771
K.I. Paraskevas, C.D. Liapis and D.P. Mikhailidis
[Abstract]
Histone Deacetylase Inhibitors as Potent Modulators
of Cellular Contacts Pp. 773-787
M. Vinken, P. Peggy, R. Vera and V. Tamara
[Abstract]
Abstracts
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to top]
EDITORIAL
Chronic obstructive respiratory diseases, such as bronchial
asthma and chronic obstructive pulmonary disease (COPD) are
related to potential numerous causes (Fig. 1)
and belong to the major growth areas of pharmacology and pharmaceutics
and there is a large variety of new compounds currently in
development.
Fig. (1).
These new agents include both substances that represent improvements
of existing classes of drugs such as corticosteroids or beta
2 receptor agonists and completely new classes of drugs. These
new classes have been developed in the past years due to an
improved understanding of the complex pathophysiology of obstructive
airway diseases and include agonists and antagonists of specific
extracellular and intracellular mediators such as cytokines
or chemokines.
Bronchial asthma displays an important health care problem,
as it exerts a tremendous toll on patients, health care providers,
and the societies. The substantial increase in the prevalence
of obstructive airway diseases in recent decades has generated
sizable concern from both domestic and global perspectives.
Epidemiologically, the incidence of allergic diseases, including
bronchial asthma has increased in developed countries over
the past several decades and these diseases comprise a large
component of the work of general practices. Also, in the pediatric
sector, asthma-like syndromes represent the most frequent
cause of hospitalization in children in western countries.
The socio-economic effect of these diseases are high and still
increasing. In 1996, 17 million US-Americans, with approximately
one third of those being children, were affected by bronchial
asthma and the economic burden of the disease is increasing
in parallel, from an estimated US$6.2 billion in 1990 to US$12.7
billion in 1998 [1]. These costs include direct medical costs
(58%) as well as indirect costs (42%) such as school days
lost, loss of work, housekeeping and mortality [1]. Initially
identified as a new major medical and socio-economic burden
in developed countries, the increase in asthma prevalence
is now also becoming more evident in rapidly developing countries
in the Third World and in emerging Second World countries
transiting to First World economic status and. As an example,
the prevalence of asthma has increased in Bangalore, India,
a city known for its high asthma prevalence, from 9.0% of
the pediatric population in 1979 to 29.5% in 1999 [1]. Similar
trends are reported from other parts of the Asian region,
such as China. Based on prevalence rates at present and projected
increases, it can be estimated that the total population of
asthmatic patients in China will be around 150 million, including
38 million children, by the year 2013. These epidemiologic
findings point to considerable challenges for public health
not only in the developed countries, but globally [2]. With
regard to the spiraling treatment costs it is currently debated
that there should be a substantial realignment of drug development
policy in the pharmaceutical industry and parallel shift in
the licensing policy by authorities to encourage the development
of novel compounds that are effective in halting the progression
from acute to chronic forms of obstructive diseases when the
diseases first manifest in early childhood [3].
Since corticosteroids are clinically effective, relatively
safe, and easy to administer, they remain the gold standard
of anti-inflammatory treatment in bronchial asthma. However,
inhaled corticosteroids have failed to halt the progression
of the asthma epidemic and they are ineffective in the small
group of patients with glucocorticoid-dependent and -resistant
asthma.
Chronic obstructive pulmonary disease on the other hand is
mainly caused by tobacco smoking. Therefore, with very few
exceptions, smoking cessation displays the only causative
and effective treatment of COPD. In this respect, the current
pharmacological treatment options of COPD have been found
to be more or less unsatisfactory, since they do not influence
the natural course or disease severity significantly. In COPD
patients without concomitant asthma glucocorticoids are scarcely
effective. While bronchodilators may improve symptoms and
quality of life in COPD patients, they do not significantly
influence the natural course of COPD with the exception of
tiotropium and only theophylline has been demonstrated to
have significant effects on airway inflammation in patients
with COPD.
It is also important to mention that the pharmacologic treatment
options are not curative but current and future approaches
may lead to a better long-term control of chronic airway obstruction.
In this respect, it is a major aim to develop novel agents
that are as effective existing drugs but have less side effects
and have a better route of administration [4, 5].
The present theme issue of Current Drug Targets aims
to provide a series of reviews that focus on current aspects
of respiratory drug development.
The series starts with an article about the use of nanoparticles
in respiratory medicine since nanoparticles are at the leading
edge of the rapidly developing field of nanotechnology with
many possible future applications in respiratory medicine
[6]. Due to their unique size-dependent properties, they offer
the possibility to develop both new therapeutic and diagnostic
tools and the ability to incorporate drugs into detectable
cell-targeted nanosystems displays a new paradigm in pharmacotherapy
that could be used for a variety of new anti-inflammatory
and anti-obstructive compounds.
The series continuous with articles describing novel strategies
including novel aspects of corticosteroid actions [7], the
role of nuclear factor kappa B in the pathogenesis of inflammatory
pulmonary diseases [8], and articles focussing targets such
as chemokines [9], cytokines [10], transcription factors [11]
and tyrosine kinase inhibition [12].
A further focus addresses targets such as adenosine and its
receptors [13] and nitric oxide synthases [14] followed by
reviews on vascular targets [15] and antioxidant therapeutic
targets [16]. Due to their recently shown implications, the
series ends with reviews about the therapeutic potential of
antimicrobial peptides [17] and the role of proteinases in
chronic inflammatory airway diseases [18].
References
[1] Sullivan, S.D. and Weiss, K.B. (2001) J. Allergy Clin.
Immunol., 107(1), 3-8.
[2] Paramesh, H. (2002) Indian J. Pediatr., 69(4),
309-312.
[3] Holt, P.G.; Sly, P.D.; Martinez, F.D.; Weiss, S.T.; Bjorksten,
B.; von Mutius, E. and Wahn, U. (2004) Nat. Immunol.,
5(7), 695-698.
[4] Groneberg, D.A.; Fischer, A.; Chung, K.F. and Daniel H.
(2004) Am. J. Respir. Cell Mol. Biol., 30(3), 251-260.
[5] Groneberg, D.A.; Witt, C.; Wagner, U.; Chung, K.F. and
Fischer, A. (2003) Respir. Med., 97(4), 382-387.
[6] Groneberg, D.A.; Giersig, M.; Welte, T. and Pison, U.
(2006) Curr. Drug Targets, 7(6), 643-648.
[7] Adcock, I.M.; Caramori, G. and Ito, K. (2006) Curr.
Drug Targets, 7(6), 649-660.
[8] Park, G.Y. and Christman, J.W. (2006) Curr. Drug Targets,
7(6), 661-668.
[9] Panina, P; Mariani, M. and D'Ambrosio, D. (2006) Curr.
Drug Targets, 7(6), 669-674.
[10] Chung, K.F. (2006) Curr. Drug Targets, 7(6),
675-681.
[11] Quarcoo, D. and Hamelmann, E. (2006) Curr. Drug Targets,
7(6), 683-689.
[12] Duan, W. and Wong, W.S.F. (2006) Curr. Drug Targets,
7(6), 691-698.
[13] Polosa, R. and Holgate, S.T. (2006) Curr. Drug Targets,
7(6), 699-706.
[14] Rahman, I. and Kilty, I. (2006) Curr. Drug Targets,
7(6), 707-720.
[15] Ricciardolo, F.L.M.; Nijkamp F.P. and Folkerts, G. (2006)
Curr. Drug Targets, 7(6), 721-735.
[16] Golpon, H.A. and Voelkel, N.F. (2006) Curr. Drug
Targets, 7(6), 737-741.
[17] Bals, R. and Hiemstra P.S. (2006) Curr. Drug Targets,
7(6), 743-750.
[18] Bühling, F.; Groneberg, D.A. and Welte, T. (2006)
Curr. Drug Targets, 7(6), 751-759.
David A. Groneberg
Otto-Heubner-Centre,
Pneumology and Immunology,
Charité School of Medicine,
Augustenburger Platz 1 OR-1,
13353 Berlin, Germany
Tel: +49-30450559055
Fax: +49-30450559951
E-mail: groneberg.david@mh-hannover.de
Tobias Welte
Department of Respiratory Diseases
Hannover Medical School
D-30623 Hannover
Germany
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Nanoparticle-Based Diagnosis and Therapy
D.A. Groneberg, M. Giersig, T. Welte and U. Pison
Nanoparticles are at the leading edge of the rapidly
developing field of material science in nanotechnology with
many potential applications in clinical medicine and research.
Due to their unique size-dependent properties nanoparticles
offer the possibility to develop both new therapeutic and
diagnostic tools.
The ability to incorporate drugs into nanosystems displays
a new paradigm in pharmacotherapy that could be used for cell-targeted
drug delivery. Nontargeted nanosystems such as nanocarriers
that are coated with polymers or albumin and solid lipid particles
have been used to transport a large number of compounds. However,
nowadays drugs can be coupled to nanocarriers that are specific
for cells and/or organs. Thus, drugs that are either trapped
within the carriers or deposited in subsurface oil layers
could be specifically delivered to organs, tumors and cells.
These strategies can be used to concentrate drugs in selected
target tissues thus minimizing systemic side effects and toxicity.
In addition to these therapeutic options, nanoparticle-based
"molecular” imaging displays a field in which this
new technology has set the stage for an evolutionary leap
in diagnostic imaging. Based on the recent progress in nanobiotechnology,
nanoparticles have the potential to become useful tools as
therapeutic and diagnostic tools in the near future.
[Back to top]
New Insights into the Molecular Mechanisms of Corticosteroids
Actions
I.M. Adcock, G. Caramori and K. Ito
Corticosteroids produce a marked improvement in clinical
parameters in most asthmatic patients; in contrast, corticosteroids
have little effect on lung function measurements in patients
with chronic obstructive pulmonary disease. By uncovering
the reason for this paradox, it should be possible to implement
treatment regimens that restore corticosteroid sensitivity.
Corticosteroids exert their effects by binding to a cytoplasmic
receptor, which is subjected to post-translational modifications.
Receptor phosphorylation may influence hormone binding and
nuclear translocation, alter glucocorticoid receptor interactions
and protein half-life. Other modifications such as nitration/nitrosylation
may also affect glucocorticoid receptor function. Oxidative
stress due to cigarette smoke may be a mechanism for the corticosteroid
resistance observed in chronic obstructive pulmonary disease,
as it enhances proinflammatory transcription and reduces glucocorticoid
receptor-associated repressor functions. Therapies targeting
these aspects of the glucocorticoid receptor activation pathway
may reverse steroid resistance in patients with chronic obstructive
pulmonary disease.
[Back to top]
Nuclear Factor Kappa B is a Promising Therapeutic
Target in Inflammatory Lung Disease
G.Y. Park and J.W. Christman
Nuclear factor kappa B (NF-κB)
regulates the transcription of a wide array of gene products
that are involved in the molecular pathobiology of the lung.
Three lung cell types, epithelial cells, macrophages and neutrophils,
have been shown to be involved in the generation of lung inflammation
through signaling mechanisms that are dependent on activation
of the NF-κB
pathway. The basic molecular biology of the NF-κB
activation pathway is well described, and approaches to modify
this axis have involved inhibition of various components of
the classical activation pathway, including ubiquitination
and proteosomal degradation of IκB.
Recently, there have been detailed characterizations of molecular
mechanisms that involve reversible post-translational modification
of RelA, including phosphorylation and acetylation that might
be amenable to therapeutic interdiction. Alternately DNA decoy,
antisense and siRNA technologies that interfere with NF-κB
binding and inhibition of gene expression, respectively, of
NF-κB
proteins have been employed in experimental settings, but
this has not been practically or effectively applied in human
disease. A very promising approach, in our view, is inhibition
of inhibitory kappa B kinases (IKK) since these appear to
be highly specific for the NF-κB
activation pathway and amenable to conventional small molecule
pharmaceutical approaches.
[Back to top]
Chemokine Receptors in Chronic Obstructive Pulmonary
Disease (COPD)
P. Panina, M. Mariani and D. D’Ambrosio
Chronic obstructive pulmonary disease (COPD) is a debilitating
disease characterized by recurrent episodes of leukocyte infiltration
in the lung parenchyma causing progressive pulmonary tissue
damage and loss of function. Recruitment of neutrophils and
CD8+ T cells is linked to disease progression and
is under control of chemotactic mediators produced in the
inflamed COPD lung. Recent progress in elucidation of the
molecular mechanisms that regulate migration of inflammatory
cells into the lung has revealed interesting novel targets
for therapeutic intervention in this disease. Chemokine receptors
CXCR1 and CXCR2 expressed on neutrophils and CXCR3 expressed
on CD8+ T cells have been identified as potential
therapeutic targets to prevent recruitment of pathogenic cells
into the inflamed lung. However, the observation that chemokine
receptors are also expressed and functional on various types
of lung resident cells including epithelial and smooth muscle
cells has raised new questions on the role played by chemokine
receptors in COPD. These new findings suggest that chemokine
receptor signalling could contribute to the adaptive response
of lung tissue resident cells to the microenvironmental changes
induced by inflammation. Thus, investigation of the role played
by chemokine receptors in development of COPD remains a fertile
area of research. Nevertheless, validation of chemokine receptor
targets in COPD has proven a difficult challenge given the
lack of predictive animal models of the disease and the still
poorly defined etiology and pathogenesis.
[Back to top]
Cytokines as Targets in Chronic Obstructive Pulmonary
Disease
K.F. Chung
Chronic obstructive pulmonary disease [COPD] is characterised
by airflow limitation of peripheral airways that is not fully
reversible and progressive and is associated with an abnormal
inflammatory response of the lungs to noxious particles or
gases. There is also intense airway wall remodelling and evidence
of systemic inflammation. Increased inter-leukin [IL]-6, IL-1β,
tumor necrosis factor-α
[TNF-α
], GRO-α
, MCP-1 and IL-8 levels are measured in sputum, with
fur-ther increases during exacerbations. The bronchiolar epithelium
over-expresses MCP-1, MIP-1α
and IL-8. IL-8 can account for sputum neutrophil chemotactic
activity. TNFα
and IL-1β
stimulate macrophages to produce matrix metallopro-teinase-9
[MMP-9], and bronchial epithelial cells to produce extracellular
matrix glycoproteins. Increased expression of transforming
growth factor-β
[TGFβ)
and epidermal growth factor [EGF] occurs in the epithelium
and submucosal cells; gene array studies reveal an excess
of TGFβ1,
CTGF and PDGFRA in COPD. TGFβ
and EGF activate proliferation of fibroblasts, while activation
of the EGF receptor leads to mucin gene expression. Anti-cytokine
therapy could be in the form of soluble receptors or by neutralising
antibodies, small compounds blocking cytokine receptors or
incomplete and non-activating cytokines, inhibitors of protein
activation and inhibitors of signal transduction and transcription
such as via inhibition of mitogen-activated protein
kinases [MAPK] and of transcription factor, nuclear factor
κB.
Anti-IL-8 therapy has been tried with little effect on COPD,
and current trials are on-going with TNF-α
inhibitors. Other treatments such as phosphodiesterase
4 inhibitors have anti-cytokine effects that may underlie
their beneficial effects in COPD.
[Back to top]
Targeting Transcription: A New Concept of Anti Inflammatory
Therapy of Airway Diseases
D. Quarcoo and E. Hamelmann
Most pathological conditions that result in human diseases
are associated with altered gene expression. With the advent
of new technologies that might control gene expression and
a broader knowledge of transcription factors and pathways,
new strategies have emerged that offer promising first results
for therapeutical and experimental purposes. This review will
focus on different inflammatory conditions of the lung, in
which targeting the transduction of involved genes have been
successfully attempted.
[Back to top]
Targeting Mitogen-Activated Protein Kinases for Asthma
W. Duan and W.S.F. Wong
Allergic asthma is a chronic airway inflammatory disorder
attributable to T-helper 2 cell responses together with other
inflammatory cells such as mast cells, B cells and eosinophils,
and pro-inflammatory cytokines and chemokines. Mitogen-activated
protein kinase (MAPK) signaling cascades have been shown to
be important in the differentiation, activation, proliferation,
degranulation and migration of various immune cells, and airway
smooth muscle and epithelial cells. In mammal, MAPK signaling
modules are divided into at least 3 groups: extracellular
signal-regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal
kinase (JNK). Each MAPK module plays a discrete yet complementary
role in accentuating allergic airway inflammation. Cumulative
evidence reveals potential anti-inflammatory activities of
MAPK inhibitors in a variety of in vitro models of
inflammation. Recently, the anti-inflammatory effects of MAPK
kinase inhibitor (U0126), p38 MAPK inhibitors (SB239063 and
respirable p38α
MAPK antisense oligonucleotide) and JNK inhibitor
(SP600125) have been demonstrated in in vivo animal
models of asthma. Development of inhibitors targeting at MAPK
could be an attractive strategy for the treatment of asthma.
[Back to top]
Adenosine Receptors As Promising Therapeutic Targets
for Drug Development in Chronic Airway Inflammation
R. Polosa and S.T. Holgate
A growing body of evidence has emerged in support of a pro-inflammatory
role for adenosine in the pathogenic mechanisms of chronic
inflammatory disorders of the airways such as asthma and COPD.
The demonstration that adeno-sine enhances mast cell allergen-dependent
activation, the notion that elevated levels of adenosine are
present in chronically inflamed airways, and the results from
exposure studies of nebulised adenosine showing dose-dependent
broncho-constriction in subjects with asthma and COPD, emphasise
the importance of adenosine in the initiation, persistence
and progression in these common inflammatory disorders of
the airways.
Adenosine exerts its manifold biological activities by interacting
with at least four adenosine receptor subtypes. Selective
activation or blockade of these sites is being exploited by
the pharmaceutical industry in an attempt to generate novel
therapies for asthma and COPD.
This review article intends to address the potential role
of adenosine in asthma and to put forward the idea that drugs
that have been developed to selectively activate or downregulate
adenosine receptor subtypes may constitute a considerable
advance in the management of chronic airway inflammation.
[Back to top]
Antioxidant Therapeutic Targets in COPD
I. Rahman and I. Kilty
Oxidative stress and chronic inflammation are important
features in the pathogenesis of chronic obstructive pulmonary
disease (COPD). Oxidative stress has important consequences
for several elements of lung physiology and for the pathogenesis
of COPD, including oxidative inactivation of antiproteases
and surfactants, mucus hypersecretion, membrane lipid peroxidation,
alveolar epithelial injury, remodeling of extracellular matrix,
and apoptosis. Therefore, targeting oxidative stress with
antioxidants or boosting the endogenous levels of antioxidants
is likely to be beneficial in the treatment of COPD. Antioxidant
and/or anti-inflammatory agents such as thiol molecules (glutathione
and mucolytic drugs, such as N-acetyl-L-cysteine and N-acystelyn),
dietary polyphenol (curcumin-diferuloylmethane, a principal
component of turmeric), resveratrol (a flavanoid found in
red wine), green tea (theophylline and epigallocatechin-3-
gallate), ergothioneine (xanthine and peroxynitrite inhibitor),
quercetin, erdosteine and carbocysteine lysine salt, have
been reported to control NF-κ
B
activation, regulation of glutathione biosynthesis genes,
chromatin remodeling and hence inflammatory gene expression.
Specific spin traps such as α-phenyl-N-tert-butyl
nitrone, a catalytic antioxidant (ECSOD mimetic), manganese
(III) meso-tetrakis (N,N'-diethyl-1,3-imidazolium-2-yl) porphyrin
(AEOL 10150 and AEOL 10113), and a SOD mimetic M40419 have
also been reported to inhibit cigarette smoke-induced inflammatory
responses in vivo. Since a variety of oxidants, free
radicals and aldehydes are implicated in the pathogenesis
of COPD it is possible that therapeutic administration of
multiple antioxidants will be effective in the treatment of
COPD. Various approaches to enhance lung antioxidant capacity
and clinical trials of antioxidant compounds in COPD are discussed.
[Back to top]
Nitric Oxide Synthase (NOS) as Therapeutic Target
for Asthma and Chronic Obstructive Pulmonary Disease
F.L.M. Ricciardolo, F.P. Nijkamp and G. Folkerts
In the respiratory tract, NO is produced by residential and
inflammatory cells. NO is generated via oxidation
of L-arginine that is catalysed by the enzyme NO synthase
(NOS). NOS exists in three distinct isoforms: neuronal NOS
(nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS).
NO derived from the constitutive isoforms of NOS (nNOS and
eNOS) and other NO-adduct molecules (nitrosothiols) are able
to modulate bronchomotor tone. NO derived from the inducible
isoform of NO synthase, up-regulated by different cytokines
via NF-κ
B dependent pathway, seems to be a pro-inflammatory
mediator with immunomodulatory effects. The production of
NO under oxidative stress conditions secondarily generates
strong oxidising agents (reactive nitrogen species) that may
amplify the inflammatory response in asthma and COPD. Moreover,
NO can be exhaled and levels are abnormal in stable atopic
asthma and during exacerbations in both asthma and COPD. Exhaled
NO might therefore be a non-invasive tool to monitor the underlying
inflammatory process. It is suggested that NOS regulation
provides a novel target in the prevention and treatment of
chronic inflammatory diseases of the airways such as asthma
and COPD.
[Back to top]
The Vasculature as a Target in the Treatment of Pulmonary
Emphysema
H.A. Golpon and N.F. Voelkel
Pulmonary emphysema, a major component of chronic obstructive
pulmonary diseases, is a highly prevalent progressive tissue-destructive
disease, with no effective treatments. The interplay between
inflammation, matrix proteolysis, oxidative stress and apoptosis
might account for the irreversible progression of the disease.
Recent investigations have underlined the importance of the
lung vasculature in the pathobiology of chronic obstructive
pulmonary diseases offering new therapeutic strategies. This
review will focus on the pulmonary microvessels as a target
in the treatment of pulmonary emphysema.
[Back to top]
Antimicrobial Peptides in COPD - Basic Biology and
Therapeutic Applications
R. Bals and P.S. Hiemstra
A large number of studies have implicated activation of innate
immune mechanisms in the pathogenesis of chronic obstructive
pulmonary disease (COPD). Accumulation of inflammatory cells,
chemokines and pro-inflammatory cytokines is a hallmark of
activation of these mechanisms, but only a few studies have
focussed on antimicrobial peptides in COPD. These peptides
are a central component of innate immunity, and airway epithelial
cells and neutrophils in the lung are the main cellular sources.
In addition to their direct antimicrobial action, antimicrobial
peptides have been shown to display a variety of activities
that may implicate them in the pathogenesis of COPD. This
is based on the observation that they not only contribute
to defense against respiratory pathogens that have been associated
with COPD, but may also contribute to the influx of inflammatory
cells, activation of adaptive immunity and epithelial remodeling.
The aim of this review is to provide an update on the basic
biology of antimicrobial peptides in the lung, with a focus
on their putative role in COPD. In addition, the implication
of this knowledge for future treatment of COPD is discussed.
[Back to top]
Proteases and Their Role in Chronic Inflammatory Lung
Diseases
F. Bühling, D. Groneberg and T. Welte
Proteases play an essential role in modulating the turnover
of extracellular matrix. Furthermore, they are involved in
the processing of various proteins thus regulating fundamental
cellular functions such as apoptosis, cells growth and activation,
protein secretion and phagocytosis. At the tissue and organ
levels, proteases influence mechanisms including cell migration
and invasion, cellular interactions and signal transduction
as well as tissue formation and stabilization. Proteases are
classified based on their catalytic mechanisms into serin,
aspartic, metallo, threonin and cysteine proteases and are
localized extracellularly, at the cellular surface, in the
cytoplasm of cells or within specific subcellular structures
such as lysosomes. The present review focuses on the specific
functions of lysosomal cysteine proteases and the potential
effects of modulators of cysteine protease activity.
[Back to top]
Leptin: A Promising Therapeutic Target with Pleiotropic
Action Besides Body Weight Regulation
K.I. Paraskevas, C.D. Liapis and D.P. Mikhailidis
Leptin seems to regulate various physiological mechanisms
besides body weight. Leptin plays a role in vascular biology
and pathology as well as renal function. In addition, leptin
has been implicated in the regulation of fertility and reproduction.
The effect of pharmaceutical agents on circulating plasma
leptin levels has been assessed. Among the drugs investigated
are glitazones, statins, fibrates, serotonin reuptake inhibitors
and cannabinoid-1 receptor antagonists. Since these agents
are used to treat pathological conditions there is a potential
role for leptin in these states.
The degree of involvement of leptin in several pathophysiological
states needs to be defined to aid in the development of potentially
useful therapeutic agents.
[Back to top]
Histone Deacetylase Inhibitors as Potent Modulators
of Cellular Contacts
M. Vinken, P. Peggy, R. Vera and V. Tamara
Histone deacetylase inhibitors are nowadays considered as
promising anti-cancer drugs, as they interfere with several
key steps of tumor development and progression, both in
vitro and in vivo. Less attention has been paid
to their impact on cell junctions. Nevertheless, cell junctions
are gatekeepers in the management of tissue homeostasis, and
their aberrant expression and functioning is observed in all
aspects of cancer biology. The present review provides a state
of the art of the current knowledge concerning the effects
of histone deacetylase inhibitors on cell junctions. Besides
an updated theoretical basis, we also exemplify its actual
relevance in cancer therapy.
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