Inflammation & Allergy-Drug Targets (Discontinued) - Volume 6, Issue 1, 2007

In general, the editions of “Inflammation & Allergy - Drug Targets” accompany an Editorial only in case of a hot topic issue, which is usually put together by a Guest Editor. In this first edition of volume 6, I thought it worthwhile to provide editorial comments, irrespective of this being a general issue, on the disparate review articles that comprise this edition. One plausible reason for this is that the breadth of topics covered by the 8 reviews judiciously reflects on the intent of this journal to cover new and exciting aspects of inflammation and allergy research, which are at the forefront of new treatments and new therapeutic targets. In addition, this journal's Editorial staff, comprising of eminent researchers and scientists from and so we have throughout the Americas, Europe, Asia and Australia, also aims at a global reach in parallel with global relevance, with this edition representing a true mirror of the quality articles from these regions. The current edition also highlights the diversity of therapeutic areas in which inflammation is a critical component. New therapeutic targets for allergic inflammation are outlined in the reviews on Interleukin-21 and c-Kit by Fina et al. and by Jensen et al. respectively. The ability to harness and understand the pleiotropic effects of statins are becoming increasingly important. Ghittoni and colleagues provide a timely review of the role of statins on T lymphocyte function and how this may be addressed therapeutically. To date, the therapeutic promise of PDE4 inhibitors as therapy in COPD and asthma has largely remained unrealized due to the manifestation of side effects such as nausea and emesis. Baumer et al. review how targeting PDE4 inhibitors for skin disease may provide therapeutic benefit with an acceptable side effect profile. Atherosclerosis remains a major problem in the developed countries and has considerably increased with an increase in the cases of metabolic diseases. Therefore the review by Wollard & Chin-Dusting on how interfering early on in the atherosclerotic cascade by targeting Pselectin may be of benefit appears timely enough. The HIV epidemic has brought a renewed need to understand and how to treat latent tuberculosis infection. This topic is successfully covered by Cardona. Current asthma therapy is dominated by the use of beta agonists and steroids. One criticism that is often leveled at these therapies is that they have little impact on the vascular remodeling that occurs in asthma. The review by Chetta et al. elucidates on how this may be tackled pharmacologically. There are very few treatment options available for acute hepatic disease. The review by Haddish-Berhane and colleagues is an interesting and novel departure from the usual review. They describe an in silico approach for estimating how treatments for inflammatory bowel disease may exert their influence. While several iterations of these approaches will need to occur before they become valuable predictors, it is likely that in silico approaches such as this will become much more prevalent and useful in drug discovery in the future. I trust that you will find this edition of IA-DT thought-provoking and informative reading. I encourage you to submit proposals for review articles, or if you wish to be a Guest Editor for a thematic issue, to myself or one of the regional editors whose contact information can be found at http://www.bentham.org/iadt.

Statins are cholesterol-lowering drugs extensively used for primary and secondary prevention of cardiovascular events related to hypercholesterolemia. Because of their capacity to inhibit HMG-CoA reductase, statins also block the production of isoprenoids required for post-translational modification of proteins such as Ras superfamily GTPases, which are master regulators in signaling pathways triggered by surface receptors. As such, statins have pleiotropic effects on many cell types. In the immune system, statins harbor strong anti-inflammatory properties, which result from their capacity to interfere with the activation of proinflammatory cells, including macrophages and endothelial cells. More recently, T-lymphocytes have been identified as cellular targets of statins. Here we shall review recent findings, which document an inhibitory activity of statins on T-cell activation, proliferation, differentiation to Th1 cells and migration across the bloodbrain barrier. The therapeutic perspectives of these findings, based on animal models and ongoing clinical trials, will also be discussed.

The phosphodiesterase (PDE) 4 is the predominant cyclic AMP degrading enzyme in a variety of inflammatory cells including eosinophils, neutrophils, macrophages, T cells and monocytes. In addition, this enzyme is expressed in non-immune cells such as keratinocytes and fibroblasts. Highly selective PDE4 inhibitors are currently under evaluation for the treatment of asthma and/or chronic obstructive pulmonary disease. Due to the broad anti-inflammatory/immunomodulatory action of PDE4 inhibitors, it has been proposed that PDE4 inhibitors might also be efficacious for skin disorders such as atopic dermatitis. Consequently, PDE4 inhibitors including cilomilast and AWD 12-281 have been tested in several models of allergic and irritant skin inflammation. These PDE4 inhibitors displayed strong anti-inflammatory action in models of allergic contact dermatitis in mice, in the arachidonic acid induced skin inflammation in mice and in ovalbumin sensitised guinea pigs. The determination of cytokines in skin homogenates revealed that both Th1 as well as Th2 cytokines are suppressed by PDE4 inhibitors, indicating an anti-inflammatory activity in both the Th2 dominated acute phase as well as the Th1 dominated chronic phase of atopic dermatitis. Due to the suppression of Th1 cytokines, activity can also be expected in psoriasis. Results of early clinical trials with both topically (cipamfylline, CP80,633) and systemically (CC-10004) active PDE4 inhibitors demonstrated efficacy in atopic dermatitis and in the case of CC-10004, also in psoriasis. AWD 12-281 (GW 842470) is currently under clinical evaluation for the topical treatment of atopic dermatitis. Results concerning clinical efficacy of this potent and selective PDE4 inhibitor are anxiously awaited.

Nowadays, there is no conclusive theory explaining the latent tuberculosis infection (LTBI). LTBI is reviewed herein as a standard progression of M. tuberculosis in the context of the usual microaerobiosis present in the host's tissues and displaying their main virulent factors: slow metabolism; cell wall thickness and ability to induce intragranulomatous necrosis. Therefore, latent bacilli (LB) would be generated by the irruption of specific immunity forcing bacilli to remain in a stationary phase (SP) inside the necrotic tissue. This tissue is crucial because it maintains a stable LB population and prolongs the production of foamy macrophages which facilitate the LB escape to the alveolar spaces. In the alveolar spaces, LB will regrow and, once freed in this privileged space, they will induce new granulomas -less developed because they are better controlled by immunity. This explains the ability of LB to face the chance to be drained as a consequence of the constant cellular turnover, and to survive for a long time in the lung. This activity also supports the hypothesis that generation of active TB highly depends on the probability of the LB regrowth in a favorable zone (i.e., in the pulmonary apex). This “dynamic” hypothesis faces a more classic one (or “static”) essentially based on the presence of a “resuscitation” factor that would reactivate “dormant” bacilli in old lesions in the apex. Current possibilities for LTBI treatment are reviewed according to this “dynamic hypothesis”, from the standard chemotherapy to the introduction of therapeutic vaccines and anti-inflammatory treatments.

Tissue remodelling can affect the entire bronchial wall, including the vascular component of the mucosa, in bronchial asthma. The bronchial mucosa is more vascularized in asthmatic patients than in healthy subjects, showing an increase in the number and dimension of vessels and vascular area. In addition, vascular changes can contribute to obstructing the airway flow in asthma. Vascular Endothelial Growth Factor, a mediator derived from endothelial cells, but also from most inflammatory cells in asthma, plays a primary role in vascular remodelling and angiogenesis. Studies on lung biopsies showed that anti-asthma drugs can decrease to varying degrees the vascular component of airway remodelling in asthma. Among asthma medications, inhaled corticosteroids effectively reverse all aspects of vascular remodelling such as vasodilatation, increased vascular permeability and angiogenesis. A better knowledge of angiogenetic mechanisms in asthma will support the selection of specific medications acting on this aspect of airway remodelling. The aim of this review is to analyze the morphological aspects of the vascular component in airway remodelling in asthma, as well as its pharmacological modulation.

Existing treatments of IBD adopt targeted oral drug delivery route for delivering bioactive agents more efficiently and with fewer side effects. However, the complex and dynamic luminal environment of the GIT and major intra/ inter patient variability greatly affects treatment, resulting in variable clinical response in patients. Mathematical simulation model can be employed to consider the complex luminal environment to asses the performance of drug delivery systems for clinical efficacy. The objective of this paper was to evaluate existing targeted oral drug delivery system for the treatment of IBD subject to inter/intra patient luminal variability using in silico experiments employing previously developed mathematical model. Simulation results indicated that the average small intestinal drug release was 44±19% and 48±21% for healthy and UC subjects, respectively. The systemic absorption of drug approached 10-25% in healthy controls and 16-32% in UC subjects. Calculated drug release from the simulations for different scenario of pH and TT had a good agreement with the clinical in vivo data (13-36% and 17-35% for healthy and UC subjects, respectively). This agreement was also true for 5-ASA and its metabolite (N-acetyl-5-ASA) recovery in the colon. The computational model has a high degree of agreement with data obtained from literature. Physicians can use characteristic performance curves of different delivery systems produced in silico to select a delivery system that would work best for their patients based upon the patient's pH and transit time profiles. It also could be used by the pharmaceutical industry to improve their medicine efficacy by altering the design.

The prevalence of allergic diseases is increasing worldwide. Hence, there is continued need for novel pharmacological therapies for the treatment of these disorders. As the mast cell is one of the essential cells that contributes to the inflammation associated with allergic diseases, this cell type remains an attractive target for such pharmacological intervention. Mast cells are major players in the early phase of the allergic response since they generate and release a variety of inflammatory mediators following antigen-dependent aggregation of IgE-bound Fc??RI (high affinity IgE-receptor) on the cell surface. These mediators also contribute to the late and chronic stages of allergic inflammation. Thus, the IgE/antigen response has been a major focus in the development of new drugs targeting mast cells. The essential role that stem cell factor (SCF) and its receptor, Kit, play in mast cell biology, however, may provide us with an alternative or adjunct therapy. SCF is necessary for mast cell development, proliferation and survival, but it is also known to play a role in homing and adhesion of mast cells. Furthermore, there is an increasing amount of literature demonstrating that SCF is necessary for optimal IgE/antigen-induced mast cell degranulation and cytokine production. Several drug candidates targeting SCF and/or Kit have been studied for their anti-allergic properties. These include anti-SCF antibodies, antisense oligonucleotides, Kit inhibitors, and inhibitors of downstream signaling molecules. In this review, we provide an overview of the role of SCF and Kit in mast cell activation and discuss potential drug candidates for targeting this response.

Interleukin-21 (IL-21) is a newly described cytokine, produced by activated CD4+ T cells. Since the discovery in 2000, IL-21 has been the object of intensive research because of its homology to IL-2, IL-4 and IL-15, and its ability to modulate both innate and adaptive immune responses. IL-21 mediates its functions through a heterodimeric receptor, composed of a specific subunit, termed IL-21 receptor (IL-21R) and the common γ-chain, that is shared with IL-2, IL-4, IL-7, IL-9, IL-13, and IL-15 receptors. IL-21R is originally described on T, B and NK cells, which is in accordance with the cell types that mostly respond to IL-21. Indeed, IL-21 augments the proliferation of CD4+ and CD8+ T lymphocytes and regulates the profile of cytokines secreted by these cells, drives the differentiation of B cells into memory cells and terminally differentiated plasma cells, and moreover, enhances the activity of natural killer cells. More recently, IL-21R has also been documented on non-immune cells, raising the possibility that IL-21 is an important mediator in the crosstalk between immune and non-immune cells. As discussed in this review, the potential role of IL-21 in immune-mediated and allergic diseases would seem to suggest that either disrupting or enhancing IL-21 signaling may be useful in specific clinical settings.

P-selectin is an inflammatory adhesion molecule expressed on activated platelets and endothelial cells. The role of inflammatory cells and adhesion molecules in the development and progression of vascular diseases has been well studied in the past two decades and it is now recognised that many of the cellular and molecular events that underlie atherosclerotic vascular disease are inflammatory in nature. The critical role of P-selectin in both leukocyte recruitment and vascular disease progression has been confirmed in knockout animal models, where P-selectin knockout mice crossed with apoE deficient mice exhibit significantly reduced atherosclerosis and leukocyte recruitment in the plaque. Being the primary adhesion molecule in initiating cell activation and cell adhesion to platelets and endothelial cells, P-selectin is therefore an attractive therapeutic target in vascular disease. However the basic tenet of targeting P-selectin may be complicated by the presence of a soluble form of P-selectin (sP-selectin). sP-selectin, lacking the cytosolic/transmembrane domain, has been identified circulating in plasma and is thought to either be derived from the secretion of an alternatively spliced protein that lacks the transmembrane domain and/or from proteolytic cleavage of the membrane form, thus reflecting the activated state of both platelets and/or endothelial cells. This review will discuss the role of P-selectin in inflammatory disease particularly in atherosclerosis and will highlight current in vitro and in vivo discoveries.