Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 7, Issue 2, 2008

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 proinflammatory 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 inducedinflammation 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 inflammatory 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 antibody 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.

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.

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-tohuman 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.

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.

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.

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.

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.

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.

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.

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.

Complex viruses such as herpes, poxvirus, HIV and influenza subvert the immune system, blocking host antiviral 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 immunemodulating 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.