Inflammation & Allergy - Drug Targets

(Formerly 'Current Drug Targets - Inflammation & Allergy')

ISSN: 1871-5281

Upcoming Articles


Metal Allergens of Growing Significance: Epidemiology, Immunotoxicology, Strategies for Testing and Prevention
Giovanni Forte, Francesco Petrucci and Beatrice Bocca
[Abstract]


Non-IgE Mediated Food Allergy
Harumi Jyonouchi
[Abstract]


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
[Abstract]


New Drug Targets for Hepatitis C and Other Flaviviridae Viruses
Tuma P., Rivas P., Vispo E., Barreiro P., Puente S., Medrano J., Madejón A., Herrero M.D., Labarga P., Garcia-Samaniego J., and Soriano V.
[Abstract]


Drug Targets in Rhinoviral Infections
Gernot Rohde
[Abstract]


Drug Targets in Infections with Other Emerging Viruses: Influenza Viruses, Metapneumovirus and Hantaviruses
Donato Torre and Agostino Pugliese
[Abstract]


CD44 and its Role in Inflammation and Inflammatory Diseases
P. Johnson and B. Ruffell
[Abstract]


Controversial Effects of Non-Steroidal Anti-Inflammatory Drugs on Bone: A Review
Pooneh Salari and Mohammad Abdollahi
[Abstract]


The Airway Neurogenic Inflammation: Clinical and Pharmacological Implications
Giovanna Pisi, Dario Olivieri and Alfredo Chetta
[Abstract]


Platelet Activating Factor/Platelet Activating Factor Receptor Pathway as a Potential Therapeutic Target in Autoimmune Diseases
L.J. Edwards and C.S. Constantinescu
[Abstract]


Toll-Like Receptors and Kidney Diseases
Theodoros Eleftheriadis and Brian R. Lawson
[Abstract]


Respiratory Syncytial Virus Bronchiolitis and Asthma – Insights from Recent Studies and Implications for Therapy
Beena Mailaparambil, Ruth Grychtol, Andrea Heinzmann
[Abstract]


Migration and Function of Th17 Cells
Chang H. Kim
[Abstract]


Mechanism of Action of Flavonoids as Anti-inflammatory Agents: A Review
Permender Rathee, Hema Chaudhary, Sushila Rathee, Dharmender Rathee, Vikash Kumar and Kanchan Kohli
[Abstract]


The Role of Anaphylatoxins C3a and C5a in Regulating Innate and Adaptive Immune Responses
Qi Peng, Ke Li, Steven H. Sacks and Wuding Zhou
[Abstract]


Abstracts


[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]
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]
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]
New Drug Targets for Hepatitis C and Other Flaviviridae Viruses
Tuma P., Rivas P., Vispo E., Barreiro P., Puente S., Medrano J., Madejón A., Herrero M.D., Labarga P., Garcia-Samaniego J., and Soriano V.

The Flaviviridae family comprises the genus Flavivirus, Hepacivirus and Pestivirus. These viruses are responsible for considerable human and animal disease and mortality worldwide. Flaviviruses cause a range of acute febrile illnesses along with encephalitic or haemorrhagic diseases. Chronic hepatitis C virus (HCV) infection is the most important hepacivirus human disease and remains a global health threat with nearly 200 million carriers worldwide. Current treatment consists in the use of peginterferon alfa (pegIFN) plus ribavirin (RBV) for 24 to 72 weeks, depending on HCV genotype, baseline viral load and the achievement of rapid virological response during therapy. However, current hepatitis C therapy fails to eradicate HCV in nearly half of treated patients and is hampered by relatively serious adverse events. No effective antiviral therapy is currently available for the treatment of flaviviruses or pestiviruses. Following the relative success of antiretroviral therapy against HIV infection, rapid progresses have been made in the development of specifically targeted antiviral therapies against HCV (STAT-C) and other Flaviviridae agents. Drug discovery for HCV is currently particularly exciting, since inhibitors of the HCV serine protease and the RNA-dependent RNA polymerase have recently entered the late stages of clinical development.


[Back to top]
Drug Targets in Rhinoviral Infections
Gernot Rohde

Human Rhinoviruses (HRV) are by far the most common respiratory viruses responsible for most cases of the common cold and important pathogens in acute exacerbations of asthma and COPD. The molecular pathogenesis of HRV infection is quite completely understood. However there is still no approved specific treatment against HRV infections. The aim of this article is therefore to give an overview of the principles of rhinovirus infection, the associated therapeutic targets and to review up-to-date virus-specific clinical trials.


[Back to top]
Drug Targets in Infections with Other Emerging Viruses: Influenza Viruses, Metapneumovirus and Hantaviruses
Donato Torre and Agostino Pugliese

Among emergent and re-emergent viral infections, influenza, hemorrhagic fevers, including hantaviruses, constitute one of the major threats to human beings.

Advances in immunopathogenesis of these viral infections have improved initial supportive treatments and led to recognition and adoption of several useful antiviral agents. This review focuses on therapeutic and preventive aspects of these viral infections, and evaluates old and new promising agents are in the pipeline of pharmaceutical companies, and finally addresses therapeutic aspects in the treatment of these viral pathogens.

However, it should be stressed that only prevention based in particular on research and development of new vaccines may be able in future to control and eventually eradicate these deadly viral pathogens.


[Back to top]
CD44 and its Role in Inflammation and Inflammatory Diseases
P. Johnson and B. Ruffell

The cell adhesion molecule CD44 is expressed on the majority of immune cells and is responsible for mediating adhesion to the extracellular matrix glycosaminoglycan, hyaluronan. The binding of CD44 to hyaluronan is induced on T lymphocytes after activation by antigen and on monocytes after stimulation by inflammatory agents. Under inflammatory conditions, CD44 on endothelial cells presents hyaluronan to CD44 on activated T lymphocytes and mediates a rolling interaction under flow conditions. This rolling interaction together with chemokine signaling upregulates integrin-mediated adhesion, which induces cell arrest and leads to subsequent migration to the inflammatory site. Studies with monoclonal antibodies against CD44 in mouse models of chronic inflammatory disease showed reduced disease severity attributed to reduced leukocyte recruitment. More recent investigations, taking advantage of the availability of CD44 null mice, further established a role for CD44 in leukocyte recruitment to inflammatory sites. These studies also revealed a role for CD44 in limiting the inflammatory response and resolving inflammation in models of lung injury and hepatitis. Here we describe the contributions of CD44 and hyaluronan to an inflammatory response and discuss the role of CD44 in both promoting and resolving inflammation in various mouse models of inflammatory disease.


[Back to top]
Controversial Effects of Non-Steroidal Anti-Inflammatory Drugs on Bone: A Review
Pooneh Salari and Mohammad Abdollahi

Bone turnover is much important in normal homeostasis of body skeleton. Medications, nutritional status, and systemic illnesses may affect bone metabolism by altering biochemical mediators. Prostaglandins, especially of E and F series are much important in bone physiology by affecting osteoclastic activity and osteoblastic differentiation. In bone fracture, production of prostaglandins affects fracture healing. There is the possibility that non-steroidal anti-inflammatory drugs (NSAIDs) affect bone health by inhibiting cyclooxygenase (COX) enzymes which reduce synthesis of prostaglandins.

The aim of this paper is to review the effects of NSAIDs on bone by evaluating both animal and human studies. Using key words such as bone, bone marker, bone mineral density, NSAIDs, COX inhibitor, bone metabolism and search engines like Web of sciences, Scopus, Pubmed, and Google scholar, all relevant studies were collected.

Although NSAIDs showed anti-resorptive properties in animal studies and some few human studies, to date no conclusive result has been observed in bone formation. Some limited studies reported higher bone mineral density in daily users of NSAIDs.


[Back to top]
The Airway Neurogenic Inflammation: Clinical and Pharmacological Implications
Giovanna Pisi, Dario Olivieri and Alfredo Chetta

Bronchial airway microvasculature consists in a developed network of vessels, which plays an important role in normal homeostasis as well as in inflammatory airway processes. Its airway autonomic neural control includes cholinergic and adrenergic innervation, as well as nonadrenergic noncholinergic system. The nerve/vessel interplay is complex and not yet completely clarified. In response to inspired air conditions, the sensory nerves can recruit appropriate reflexes, which can induce different vascular processes, such as vasodilatation, vasoconstriction, plasma extravasation and exudation. Additionally, the stimulation of C fibres may result in an axon local reflex with antidromic conduction down afferent nerve collaterals and release of sensory neuropeptides, which in turn may act on the mucosal vasculature to promote vasodilatation and microvascular leakage. The neurogenic inflammation may play a key role in allergic diseases, such as asthma, as well as in COPD, a smoking-related disease. This review deals with the interactions of vessels and nerves within the airway mucosa under healthy conditions and in inflammatory diseases. The clinical and pharmacological implications are also described.


[Back to top]
Platelet Activating Factor/Platelet Activating Factor Receptor Pathway as a Potential Therapeutic Target in Autoimmune Diseases
L.J. Edwards and C.S. Constantinescu

Platelet activating factor (PAF) is a phospholipid mediator of inflammation that is released early in inflammation by a variety of cell types. PAF acts largely by binding to its receptor, PAF-R, a G-protein coupled receptor found on a variety of cells, including cells of the immune system.

PAF has been implicated in the pathogenesis of asthma and allergic conditions, but its role in autoimmune conditions has been less extensively investigated. Here, we review the accumulating evidence for the role of PAF/PAF-R pathway in autoimmune diseases. We describe studies showing up-regulation of PAF-R in inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis and review the evidence from the use of PAF-R antagonists. We describe results of experimental models of inflammatory diseases that point to a role for PAF/PAF-R pathway including those using PAF-R antagonists and those employing PAF-R knockout mice and knockout mice for cytosolic phospholipase2.

Recent experiments from our laboratory show that PAF/PAF-R pathway may influence T cell responses and favour the Th17 phenotype (in which T cells produce tissue destructive proinflammatory cytokine IL-17).

The PAF/PAF-R pathway is a promising target for pharmacological intervention in autoimmune diseases.


[Back to top]
Toll-Like Receptors and Kidney Diseases
Theodoros Eleftheriadis and Brian R. Lawson

Toll like receptors (TLRs) have been extensively studied since their discovery in 1997, and an increasingly detailed picture is emerging about their role in health and disease. TLRs, the first identified family of pattern recognition receptors, can recognize invaders through the exogenous pathogen-associated molecular patterns (PAMPs) and tissue injury through the endogenous danger-associated molecular patterns (DAMPs). In addition to immunocytes, TLRs are widely distributed in various cell types, including renal cells where they are thought to play a significant role in immune activation to pathogens, as well as the development and course of various kidney pathologies. This review summarizes the present data about the important role TLRs play in kidney diseases focusing on the specific role of PAMPs versus DAMPs and of local versus systemic TLR activation.


[Back to top]
Respiratory Syncytial Virus Bronchiolitis and Asthma – Insights from Recent Studies and Implications for Therapy
Beena Mailaparambil, Ruth Grychtol, Andrea Heinzmann

Infection with respiratory syncytial virus (RSV) is a leading cause of upper and lower respiratory tract infection in infants. It is accompanied by a considerably disease burden and a hospitalisation rate of up to 3% in infected infants. Besides, it is still a matter of intensive discussion whether severe RSV infection in early infancy causes the development of asthma later in live or whether RSV bronchiolitis just chronologically precedes asthma in children who are susceptible to asthma. The latter could be due to a common genetic background of both diseases predisposing to an exaggerated inflammatory response of the lungs to allergens and pathogens.

Genetic studies might help to elucidate the mechanisms leading to both diseases and to highlight common as well as diverse pathways. The results of such investigations will influence the current understanding of the diseases and might even change our therapeutical approaches to both disorders.

This review summarizes current findings in the genetics of bronchial asthma and severe RSV bronchiolitis. The question whether a relationship exists between severe RSV bronchiolitis in infancy and childhood asthma will also be discussed by taking recent epidemiological studies in account. A special focus is laid on the implications of these findings for a targeted drug therapy of both diseases.


[Back to top]
Migration and Function of Th17 Cells
Chang H. Kim

T cells play central roles in regulation of the immune system in mammals. T cell receptor α β T cells that can produce the cytokine IL-17 are called Th17 cells and form a lineage of effector T cells that are distinct from Th1, Th2 and FoxP3⁺ T cells. The primary function of Th17 cells is to fight infection by bacterial and fungal pathogens. Autoreactive Th17 cells are implicated in mediating inflammation in the central nerves system, joints and other tissues. Th17 cells express a number of chemokine receptors including a secondary lymphoid tissue homing receptor (CCR7), the B follicle homing receptor (CXCR5), and non-lymphoid tissue homing receptors (CCR4, CCR5, and CXCR6). While these receptors are heterogeneously expressed by Th17 cells and have the potential to guide the migration of Th17 cell subsets into various tissues, CCR6 is uniformly expressed by most Th17 cells regardless of their tissue tropism. CCR6 plays an important role in migration of Th17 cells to inflamed tissues. Another function of CCR6 is to localize Th17 cells close to CCL20 expressing cells in the intestine, which would be important for the homeostasis of Th17 cells. Thus, chemokine receptors appear to play complex roles in the biology of Th17 cells.


[Back to top]
Mechanism of Action of Flavonoids as Anti-inflammatory Agents: A Review
Permender Rathee, Hema Chaudhary, Sushila Rathee, Dharmender Rathee, Vikash Kumar and Kanchan Kohli

Flavonoids are polyphenolic compounds that occur ubiquitously in plants having a variety of biological effects both in vitro and in vivo. They have been found to have antimicrobial, antiviral, anti-ulcerogenic, cytotoxic, anti-neoplastic, mutagenic, antioxidant, antihepatotoxic, antihypertensive, hypolipidemic, antiplatelet and anti-inflammatory activities. Flavonoids also have biochemical effects, which inhibit a number of enzymes such as aldose reductase, xanthine oxidase, phosphodiesterase, Ca⁺²-ATPase, lipoxygenase, cycloxygenase, etc. They also have a regulatory role on different hormones like estrogens, androgens and thyroid hormone. They have been found to have anti-inflammatory activity in both proliferative and exudative phases of inflammation. Several mechanisms of action have been proposed to explain anti-inflammatory action of flavonoids. The aim of the present review is to give an overview of the mechanism of action of potential anti-inflammatory flavonoids.


[Back to top]
The Role of Anaphylatoxins C3a and C5a in Regulating Innate and Adaptive Immune Responses
Qi Peng, Ke Li, Steven H. Sacks and Wuding Zhou

C3a and C5a, the small (~10KDa) cleavage fragments released by complement activation, are potent mediators of inflammation. They are anaphylatoxins and act as cell activators with nanomolar affinity, exerting their functions through binding to specific receptors (C3aR and C5aR or C5L2 respectively). Recent studies suggest that locally generated complement effector molecules including C3a and C5a contribute to pathological processes in inflammatory and immunological diseases as well as adaptive immune response besides its host defence mechanism. Targeting the receptors and/or their ligands can reduce undesired inflammatory responses and tissue damage in certain pathological conditions. In this article we describe the recent developments in this important area and focus on the role of C3a/C5a in inflammatory and autoimmune diseases and in adaptive immune responses.