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Anti-Inflammatory
& Anti-Allergy Agents in Medicinal Chemistry
ISSN: 1871-5230
Anti-Inflammatory & Anti-Allergy
Agents in Medicinal Chemistry
Volume 7, Number 2, June 2008
Contents
Avian and Pandemic Influenza Cytokine Storm,
Inflammation, Tissue and Therapeutic Opportunities
Guest Editor: Jonathan P. Wong
Editorial Pp. 58
Role of Apoptosis and Proinflammatory Cytokines in
Influenza Virus Morbidity and Mortality Pp. 59-70
Susan Jane Morris, Edward William Andrew Brydon and Clive
Sweet
[Abstract] [Purchase
Article]
The Induction of Proinflammatory Cytokines in Response
to Avian Influenza H5N1 Infections and their Role in Pathogenesis
and the Enhancement of Virulence Pp. 71-80
Mark D. Wareing and Gregory A. Tannock
[Abstract] [Purchase
Article]
Pathogenicity of the 1918 Pandemic Influenza
Virus Pp. 81-86
M. Suresh and Darwyn Kobasa
[Abstract] [Purchase
Article]
Role of Memory T Cells in Influenza Viral Infection
Pp. 87-96
Rabih Halwani, Mehrnoosh Doroudchi, Mohamed El-Far, Andre
Tanel, Yu Shi, Bader Yassine-Diab and Rafick-Pierre Sékaly
[Abstract] [Purchase
Article]
Mechanisms and Consequences of Phagocytosis of
Influenza Virus-Infected Cells Pp. 97-100
Yoshinobu Nakanishi, Yumi Hashimoto, Takenori Takizawa
and Akiko Shiratsuchi
[Abstract] [Purchase
Article]
Inhibition of Highly Pathogenic Avian H5N1 Influenza
Virus Replication by NanoRNA Oligonucleotides Pp.
101-105
Rod Dale, Ming Wang and Lun-Quan Sun
[Abstract] [Purchase
Article]
Antiviral Activity of Jodantipyrin – An
Anti-Inflammatory Oral Therapeutic with Interferon-Inducing
Properties Pp. 106-115
Vladimir N. Khudoley, Albert S. Saratikov, Alexei V. Lepekhin,
Valentina E. Yavorskaya, Alexandr N. Evstropov, Elena V. Portnyagina,
Albina D. Pomogaeva, Elvira I. Beloborodova, Marina A. Vnushinkaia,
Evgeni V. Schmidt, Nina V. Krilova, Dina Kh. Khunafina, Marina
V. Mezenzeva, Felix I. Ershov, Konstantin K. Raevski, Ekaterina
V. Vlasova, Gulnara A. Abdulova and Elena A. Kropotkina
[Abstract] [Purchase
Article]
Small Interfering RNAs and their Therapeutic
Applications in Mitigation of Virus Replication and Pathological
Effects in the Respiratory Tract Pp. 116-121
Murray J. Cairns
[Abstract] [Purchase
Article]
Feasibility and Prospects for Anti-Inflammatory
Antibodies in the Treatment and Disease Management of Influenza
Pp. 122-129
Wei-Gang Hu and Jonathan P. Wong
[Abstract] [Purchase
Article]
Viral Anti-Inflammatory Proteins: The Potential
for Immunotherapeutic Applications in Cancer Pp.
130-149
J.A. Davids, G. Munuswamy-Ramunujam, L.Y. Liu, E. Dai
and A. Lucas
[Abstract] [Purchase
Article]
Abstracts
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Editorial :
Despite advances in vaccine development and antiviral drug
chemotherapy, the world is still ill equipped to defend against
future influenza pandemics. The vulnerability of humans to
pandemic influenza was particularly evident during the 1918-19
Spanish flu pandemic which killed 20-50 millions people globally.
The current global bird flu crisis in Asia, Africa and Europe
has sparked fear of another influenza pandemic and again expose
our vulnerability.
The goals of this special issue entitled “Avian and
pandemic influenza: cytokine storm, inflammation, tissue injuries
and therapeutic opportunities” are two-fold. Firstly,
to provide a comprehensive review on the pathogenicity of
deadly influenza viruses and on the mechanisms virus-induced
induce massive inflammation and apoptosis in the respiratory
tract. Secondly, to present a forum to highlight therapeutic
approaches that could be used to mitigate the devastating
effects of inflammatory and apoptosis, and how they may have
a role to play in improving clinical outcome in humans.
This special issue is comprised of original and review articles
contributed by some of the leading experts in immunology,
virology, molecular biology and clinical medicine. The first
2 articles by Morris et al., and Wareing and Tannock,
outlined the immunological mechanisms of “cytokine storm”
characterized by apoptosis and overinduction of various pro-inflammatory
cytokines, which is closely linked to activation of caspase
pathway and clinical disease severity. This activation of
the pro-inflammatory cytokines and apoptosis lead to pulmonary
edema and destruction of the respiratory epithelium in various
animal models were documented using a reconstructed 1918-19
Spanish influenza virus (Suresh and Kobasa). Cellular immune
responses to influenza virus infections, particularly memory
T-cells (Halwani et al.) and phagocytes (Nakanishi et al.),
and their roles in the pathogenicity of and constituting to
protective antiviral immunity to influenza infections are
addressed.
The second part of this issue focuses on therapeutic opportunities
to counter the deadly effects on influenza viral induced-inflammation
and apoptosis. Recent clinical findings have shown that treatment
of inflammation in avian influenza patients with corticosteroid
had resulted in higher fatality rate compared to those who
did not receive corticosteroids (New Engl. J. Med. 358:261-273,
2008). It is therefore important to explore novel therapeutic
agents other than corticosteroids to counter this in-flammatory
effect and to improve survival in these patients. Dale et
al., presented promising results that provide evidence
that short nano RNA oligonucleotides directed against non-structural
viral protein are effective in the reducing the inflammatory
effects and enhancing the antiviral efficacy against the highly
pathogenic avian H5N1 influenza virus infection. V. Khudoley
et al. presented a review comprising a number of studies that
suggest Jodantipyrin, an old anti-inflammatory drug that induces
interferon, has broad-spectrum antiviral effect and has been
shown in clinical efficacy against influenza virus infections.
The articles by Cairns et al., and Hu et al.,
described novel approaches using small interfering RNAs (siRNA)
and humanized anti-body fragments to either silence the expression
of viral proteins and/or reduce virus-induced inflammation,
respectively. The potential applications of these approaches
and their efficacies will need to be determined against the
deadly influenza viruses. Davids et al., described
an important study to explore the beneficial effects of anti-inflammatory
proteins produced by viruses and how they can be used for
the treatment of cancers and prevention of angiogenesis and
metastasis.
I am privileged to have the opportunity to work with some
of the world’s leaders in these multidisciplinary and
intersecting fields to contribute to this special issue. Their
contributions provide invaluable insights and knowledge to
the challenges of defending against these deadly and ever-changing
viruses, and may therefore pave the way to develop novel countermeasures
that can be used to reduce the effects of cytokine storm and
to improve the therapeutic effectiveness against these viruses.
I wish to also express my appreciation to Prof. B Tunctan,
Editor-in-Chief, Anti-Inflammatory & Anti-Allergy Agents
in Medicinal Chemistry and Bentham Science Publishers for
the wonderful opportunity to publish this special issue. I
am also grateful to kind assistance of Saima Rao at Bentham
for the kind assistance in processing of these manuscripts.
Jonathan P. Wong
Guest Editor
Anti-Inflammatory & Anti-Allergy Agents in Medicinal
Chemistry
Defence Research and Development Canada - Suffield
Box 4000, Station Main
Medicine Hat, Alberta
Canada T1A 8K6
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Article]
Role of Apoptosis and Proinflammatory Cytokines in Influenza
Virus Morbidity and Mortality
Susan Jane Morris, Edward William Andrew Brydon and Clive
Sweet
Influenza virus is a major human pathogen that causes
epidemics and pandemics with increased morbidity and, especially
in the elderly and those with pre-existing medical conditions,
increased mortality. Currently avian influenza viruses are
causing deaths in previously “not-at-risk” groups.
Influenza is characterised by respiratory symptoms and constitutional
symptoms. In this review we explore current knowledge of the
role inflammation and apoptosis plays in respiratory epithelial
cell damage and pathogenicity. Influenza virus vRNA, other
ssRNAs and dsRNAs are recognised by cellular pathogen-associated
microbial pattern (PAMP) receptors. Of these, TLR3 activates
NF-κB,
a transcription factor of pro-inflammatory cytokines such
as TNF-α
, IL-1 and IL-6 along with a variety of chemokines like CCL2,
CCL3, CCL4, CCL5, CXCL8 and CXCL10, and Type 1 interferons
(IFN) through the IFN regulator IRF3. TLR7/TLR8 activates
NF-κB
through different mediators to stimulate a similar response.
Pro-inflammatory and antiviral cytokines may also be induced
by TLR3/TLR7-independent pathways involving NOD-like receptors
and CARD-helicase proteins. It is also becoming clearer that
the mechanisms leading to inflammatory responses and to apoptosis
are linked particularly with regard to caspase activation
and function. The role these pathways play in influenza virus
induced mortality and morbidity will be discussed with particular
reference to that of the H5N1 viruses.
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Article]
The Induction of Proinflammatory Cytokines in Response to
Avian Influenza H5N1 Infections and their Role in Pathogenesis
and the Enhancement of Virulence
Mark D. Wareing and Gregory A. Tannock
Avian H5N1 influenza viruses first emerged as members
of a new human influenza A subtype in Hong Kong in 1997 and
there are continuing concerns that members of the subtype
will be the cause of the next pandemic. Human-to-human transmission
is rare, but mortality rates associated with avian-to-human
transmission are significantly higher than for current human
epidemic strains. Severe human H5N1 infections are associated
with severe viral pneumonia, diffuse alveolar damage and reactive
hemophagocytic syndrome (RHS). A characteristic of RHS, and
one of the key determinants of H5N1-mediated pathology, is
dysfunctional cytokine production resulting in a cytokine
storm. Factors contributing to cytokine dysregulation include
viral load, apoptosis and the intrinsic properties of H5N1
virus strains. Here, we review the cytokine response to influenza
and try to address the relationship between hypercytokinemia
and severe H5N1 pathology.
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Pathogenicity of the 1918 Pandemic Influenza Virus
M. Suresh and Darwyn Kobasa
The Spanish influenza pandemic of 1918-19 was one of
three pandemics in the last century. It was exceptional among
human influenza pandemics for the severity of disease experienced
by victims of the pandemic, particularly among healthy young
adults. Following the recent reconstruction of the complete
1918 virus, examination of host responses and pathological
outcomes in animal models of infection has provided insight
into the mechanism of viral pathogenesis. The reconstructed
1918 virus is highly virulent in the macaque, mouse and ferret
models and replicates to high levels throughout the respiratory
tract. Infection results in extensive lung injury, including
severe hemorrhage and edema and destruction of the respiratory
epithelium. Host responses in the macaque and mouse include
rapid and sustained activation of proinflammatory cytokines
and chemokines that are linked to the extensive infiltration
of infected tissue by neutrophils and activated macrophages.
These responses likely exacerbate tissue damage and contribute
to the lethal outcome of infection. With recent concerns about
the potential for a pandemic caused by the highly pathogenic
avian H5N1 influenza (HPAI H5N1) virus a better understanding
of the mechanisms used by virulent viruses to cause disease
will be essential for the development and effective use of
vaccines and anti-viral therapeutics.
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Role of Memory T Cells in Influenza Viral Infection
Rabih Halwani, Mehrnoosh Doroudchi, Mohamed El-Far, Andre
Tanel, Yu Shi, Bader Yassine-Diab and Rafick-Pierre Sékaly
The major role of memory T cells is to ensure protection
upon re-exposure to pathogens through rapid clonal proliferation
and functional activation. This immunity usually persists
for periods which can extend for over 60 years. These memory
T cells are generated during acute viral infections. In the
context of influenza viral infection, the presence of neutralizing
antibodies against influenza virus proteins provides the first
line of defense that prevents viral colonization and replication.
Long-lasting humoral protective immunity is also needed for
protection. However, antibodies against one subtype are usually
inefficient in providing protection against other subtypes
in humans. Major cytotoxic T-cell responses are usually targeted
against conserved internal viral proteins. Moreover, the generated
CTL responses are cross-reactive between influenza subtypes.
In this review, we will discuss the generation and persistence
of memory T cells and the role they play during influenza
viral infection. An overview of new vaccine approaches aiming
at the development of protective T-cell immune memory against
influenza infection will also be provided.
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Mechanisms and Consequences of Phagocytosis of Influenza Virus-Infected
Cells
Yoshinobu Nakanishi, Yumi Hashimoto, Takenori Takizawa
and Akiko Shiratsuchi
Influenza virus-infected cells are induced to undergo
apoptosis and become susceptible to phagocytosis. Data from
our in vitro and in vivo experiments have
suggested that 1) alveolar macrophages and neutrophils phagocytose
influenza virus-infected cells in an apoptosis-dependent manner;
2) the membrane phospholipid phosphatidylserine and viral
neuraminidase-processed carbohydrates at the surface of target
cells and phagocytes, respectively, are involved in the association
of the two types of cells; and 3) phagocytic elimination of
virus-infected cells leads to a reduction in the pathogenesis
of influenza. These findings could lead to the development
of a novel antiviral agent against influenza.
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Inhibition of Highly Pathogenic Avian H5N1 Influenza Virus
Replication by NanoRNA Oligonucleotides
Rod Dale, Ming Wang and Lun-Quan Sun
H5N1 avian influenza virus (AIV) has caused widespread
infections in poultry and wild birds, and has the potential
to emerge as a pandemic threat to human. Nucleic acid-based
drugs are promising classes of therapeutic agents that have
important clinical applications for the prevention and treatment
of viral diseases.In this review, a breif overview is made
in the use of antisense technology in gene suppression. The
main focus is on the features of a modified short RNA oligonucleotide
(nanoRNAs) and its use in suppression of H5N1 influenza viral
replication, including the design, efficacy of nanoRNAs and
the evaluation of these agents from in vitro activity
to efficacy in animal protection studies.
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Antiviral Activity of Jodantipyrin – An Anti-Inflammatory
Oral Therapeutic with Interferon-Inducing Properties
Vladimir N. Khudoley, Albert S. Saratikov, Alexei V. Lepekhin,
Valentina E. Yavorskaya, Alexandr N. Evstropov, Elena V. Portnyagina,
Albina D. Pomogaeva, Elvira I. Beloborodova, Marina A. Vnushinkaia,
Evgeni V. Schmidt, Nina V. Krilova, Dina Kh. Khunafina, Marina
V. Mezenzeva, Felix I. Ershov, Konstantin K. Raevski, Ekaterina
V. Vlasova, Gulnara A. Abdulova and Elena A. Kropotkina
Jodantipyrin or 4-iodo-1,5-dimethyl-2-phenyl-pyrazol-3-one
is an iodinated form of antipyrine which belongs to the group
of non-steroidal anti-inflammatory drugs. The parent compound,
antipyrine, is keto derivative of pyrazoline and is the oldest
known synthetic drug. The primery pharmacological activity
of Jodantipyrin is based on its properties to induce endogenous
type 1 interferons. The anti-inflammatory action of Jodantipyrin
produces several effects such as reduction of degranulation
of the mast cells; suppression of prostaglandins and arachidonic
acid synthesis; cell membrane stabilizing activity; normalization
of liver damage associated enzymes such as ALT and AST; lower
intensity of oxidation and phosphorylation processes. Discovered
direct antiviral activity is evidenced by suppression of viral
DNA and RNA synthesis in vitro and under detail investigation
in vivo. Jodantipyrin displays antiviral activity
against interferon sensitive viruses including tick-borne
encephalitis virus; hantavirus; influenza type A virus; herpes
viruses; hepatitis B and C (HBV and HCV) viruses; Coxsackie
A and B enteroviruses; papilloma virus and some others. Jodantipyrin
was approved in Russia and neighboring countries for prevention
and combinational treatment of tick-borne encephalitis (TBE)
in 1996, combinational treatment hemorrhagic fever with renal
syndrome (HFRS) in 2001, and later for prevention of seasonal
flu. The most recent data suggests that Jodantipyrin might
be effective against highly pathogenic avian influenza or
bird flu virus. As the unique anti-viral therapeutic, Jodantipyrin
is under intensive investigation as a potentially effective
agent with a specific antiviral activity.
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Small Interfering RNAs and their Therapeutic Applications
in Mitigation of Virus Replication and Pathological Effects
in the Respiratory Tract
Murray J. Cairns
Small double stranded RNA molecules known as small interfering
RNA (siRNA), initially identified for their role in the guide
sequence in the effector complex of the RNA interference pathway,
now represent a promising new class of therapeutic agent with
potentially important clinical applications for the prevention
and treatment of viral disease. siRNA with its ability to
harness the cells own gene-silencing apparatus in a highly
adaptable and sequence specific manner has demonstrated unprecedented
anti-gene activity. This review highlights the key chemical
and biological parameters of this technology and its application
in viral suppression, particularly in the respiratory tract.
This treatment site represents both an important opportunity
to establish clinical exposure for the technology, and an
important challenge to provide an additional layer of protection
against highly threatening influenza epidemics and potential
pandemics.
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Feasibility and Prospects for Anti-Inflammatory Antibodies
in the Treatment and Disease Management of Influenza
Wei-Gang Hu and Jonathan P. Wong
Influenza A virus poses a direct threat to humans and
results in the deaths of about 36,000 people each year in
USA. There is tremendous concern that highly virulent variants
of the virus may emerge and cause a major pandemic. The influenza
virus attacks the respiratory tracts and may cause acute lung
inflammation. Certain evidence suggests that the lethal effect
of the influenza virus results from inflammation of the host
lung rather than from direct viral cytopathy. This has led
to the concept that co-administration of effective antiviral
agents with inflammation attenuators, by which a reduction,
but not an elimination of inflammation would improve lung
function without compromising virus clearance, and might result
in a better treatment outcome of virulent influenza. Anti-inflammatory
antibodies are widely developed for treatment of inflammatory
diseases such as Crohn’s disease, ulcerative colitis,
rheumatoid arthritis, psoriasis and so on. This review focuses
on anti-inflammatory antibodies and discusses the feasibility
and prospects for using them to attenuate the host inflammatory
responses in the lung for the treatment and disease management
of virulent influenza.
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Viral Anti-Inflammatory Proteins: The Potential for Immunotherapeutic
Applications in Cancer
J.A. Davids, G. Munuswamy-Ramunujam, L.Y. Liu, E. Dai
and A. Lucas
Complex viruses such as herpes, poxvirus, HIV and influenza
subvert the immune system, blocking host anti-viral defenses.
The innate immune inflammatory response represents the first
line of defense against invading pathogens. This first line
of defense also initiates cellular healing after infection
or injury. With tumors, however, the innate immune response
is a classic double-edged sword, with the capacity to promote
or terminate tumor progression. The proliferation and invasion
of many cancers as well as metastasis have now been linked
with an increase in many of the molecular signals that drive
inflammation. Inflammatory responses are mediated by endothelial
cells in the arterial walls and by neutrophils, monocytes
/macrophages and T lymphocytes in the circulating blood. Activated
cells release chemokines, cytokines, serine proteases in the
thrombotic and thrombolytic pathways, apoptotic serine and
cysteine proteases, and growth factors that accelerate cellular
proliferation, migration and invasion. We are investigating
potential therapeutic applications of virus-derived immune-modulating
proteins, as immunotherapeutics for use in disease states
driven by excessive inflammatory responses. In this review
we will describe the roles of excess inflammatory responses
in cancer and discuss potential applications of viral anti-inflammatory
proteins for the treatment of cancer with special emphasis
on immune-modulating proteins that target chemokine and serine
protease pathways. These immune-modulating proteins represent
a new class of naturally occurring, virus-derived immunomodulating
drugs. While the rest of this special issue will be discussing
virus induced disease, here we will discuss the potential
for harvesting viral immune-modulating proteins as a new class
of immunotherapeutic.
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