Current Drug Metabolism - Volume 11, Issue 3, 2010

The current Hot Topic Issue, organized in two volumes, is dedicated to the very old health problem of the still incurable chronic skin pathologies, and to novel emerging approaches to pharmacological treatment. Here, we focused mainly on immune-dependent and UV-induced skin disorders with a clear inflammatory component such as psoriasis, atopic and contact dermatitis, UV-induced skin tumors, and photoaging. In the last years, the immune and molecular mechanisms underlying psoriasis, contact dermatitis and atopic dermatitis have been extensively investigated, and relevant steps in their pathogenesis as well as molecular targets for drug development have been identified. The introductory paper by Cristina Albanesi and Saveria Pastore covers these developments and especially highlights the current consensus on the dramatic role of skin keratinocytes in the inflammatory responses of the skin. Far from simply being the bricks for the construction of an effective barrier against environmental insults, keratinocytes are now considered highly active immune cells, with a major control over both the acute and the chronic phases of skin inflammation by means of cytokine/chemokine production and surface adhesion/recognition molecule expression. This introductory chapter puts special emphasis to the fact that recently introduced highly specific, single molecule-targeted biological drugs are offering the best demonstration that an accurate definition of the molecular pathways underlying any pathology is mandatory to identify the relevant therapeutic targets for drug discovery. This is utmost evident from the so-called “biological therapy” of psoriasis presently, but the same approach is under intense evaluation to improve the clinical management of contact and atopic dermatitis. According to this premise, in their review dedicated to contact dermatitis immunotherapy, Andrea Cavani and Anastasia De Luca concentrate on specific molecular pathways-targets for contact dermatitis. In particular, their paper is mainly focused on potentially effective blockers/inhibitors of the adhesion molecules involved in leukocyte-endothelial cell interaction and hence leukocyte extravasation, and against the integrins involved in the immune synapsis precipitating the disease. Finally, the authors express their expert point of view on the potential development of hapten-specific desensitization therapies in contact dermatitis, which aim at boosting and expanding the anti-inflammatory activity of regulatory T cell populations, whose physiological role is evidently compromised in sensitized individuals. Expansion of allergen-specific regulatory T cell populations should represent a valid approach also for atopic dermatitis, a chronic skin disease induced and aggravated by sensitization to environmental protein allergens in a relevant proportion of hyper-responding subjects. The contribution of Claudia Traidl and colleagues offers a complete overview of the pharmacological treatments of atopic dermatitis, which is currently based on local and/or systemic administration of anti-inflammatory drugs. These authors emphasize that, although significant gains have been made during the last years in the understanding of the molecular mechanisms behind this disease, nonetheless its treatment basically aims at symptomatic relief. However, a number of pilot experimental approaches with new drugs, including biologics that neutralize B cells or selectively bind the IgE component of immunoglobulins, is hopefully opening new therapeutic possibilities to patients with severe atopic dermatitis and concomitant sensitization to environmental allergens. The most relevant insult to human skin derives from the UV components of the solar light. It is now well ascertained that both acute and chronic exposure to solar light associates with increased risk of developing a number of pathological states, including chronic inflammation, immunosuppression and carcinogenesis. The UV-initiated molecular processes leading to transient or irreversible damage to the skin are peculiarly manifold and complex, and this fact can be easily perceived by reading the exhaustive review written by Charareh Pourzand and colleague. In particular, she draws our attention to a new molecular aspect, which is the UV-induced release of chelatable iron by cells of human skin, and its intrinsic toxicity for the cell. Iron is a critically important metal for numerous cellular functions. At the same time, abnormal increase of the unbound, labile, and redox active iron can be toxic, essentially due to the iron-catalyzed free radical-driven chain reactions, which are damaging to biologically important molecules and structures. Indeed, presence of excess iron has been recognized in severe human diseases, including neurodegenerative diseases, liver cirrhosis, and cancer, and also in inflammatory skin disorders such as psoriasis and atopic dermatitis. Among the labile iron-induced molecular targets leading to skin damage, there is a persistent NFkappaB activation, which predisposes to inflammation, skin hyperplasia and eventually carcinogenesis. The natural consequence is now the search for a valid pharmacological approach to neutralize labile iron in vivo. Updated and unique description of possible candidates, including synthetic or natural multi-antioxidant substances that should also possess relevant iron-chelating activities, or photo-activated and photo-controlled pro-drugs is provided. Being photo-sensitive, these pro-drugs will exert their activity as iron chelators in situ within the skin only at need, in response to exposure to the sunlight and hence with no perturbation of the physiological labile iron pool....

Inflammatory dermatoses encompass an enormous area of dermatopathology. These diseases are triggered and maintained by aberrant responses of the cells of the skin immune system. In the last decade it has become clear that epidermal keratinocytes are highly active immunological cells, with a major control over the acute and the chronic phase of skin inflammation by means of cytokine/ chemokine production and surface molecule expression. In their turn, these rather disease-specific events driven by keratinocytes lead to a rich inflammatory infiltrate in the whole skin including the upper layers of the epidermis, and eventually in the aggravation and/or perpetuation of the skin disorder. Recently introduced single molecule-targeted biological drugs are offering the best demonstration that a fine definition of the molecular pathways underlying skin disorders is now necessary to identify the relevant therapeutic targets and finally obtain successful treatment of these diseases. In this review, we will summarize recent progress in our understanding of the immunologic basis of psoriasis, allergic contact dermatitis and atopic dermatitis, with special emphasis on potentially effective targets for novel anti-inflammatory drugs.

Allergic contact dermatitis is a common eczematous skin disease that occurs in sensitized individuals at the site of contact with small chemicals penetrating the skin barrier. The onset of the disease is mostly due to the rapid recruitment of chemical-specific CD8+ T cells, which induce apoptosis of keratinocytes. Additionally, CD4+ Th1 and Th17 contribute to the extension of the inflammatory reaction by releasing pro-inflammatory cytokines that activate keratinocytes and other skin resident cells. The immune reaction is tightly regulated through multiple mechanisms. In particular, T cell population with regulatory function, such as T regulatory cells 1 and CD4+CD25+ T regulatory cells have a critical role in preventing the development of allergic reactions to innocuous chemicals contacting the skin, and in limiting the magnitude of the inflammatory process in already sensitized individuals. Allergic contact dermatitis is a chronic disease, which lasts, in most cases, for the entire life of the affected individual. Thus, prevention and avoidance of contact with the sensitizer are critical factors in the management of affected patients. The gold standard therapeutic approach for the disease remains the local and/or systemic immunosuppression, aimed to block T cell functions and keratinocyte responsiveness to pro-inflammatory stimuli. However, alternative approaches that aim at preventing T cell accumulation in peripheral tissues are under investigation. Most recently, disclosure of mechanisms regulating allergic contact dermatitis have provided new therapeutic perspectives for the disease, mostly based on immunomodulatory interventions, as in the case of induction of specific oral tolerance to the causative allergen.

The present review aims at giving a condensed view on the current status of therapy of atopic eczema - a common chronically relapsing inflammatory skin disease. Atopic eczema is a multifactorial disease with a tendency for chronification. Owing to the associated genetic factors, therapeutic amelioration of skin symptoms is often only transient. Therefore, treatment basically focuses on symptomatic relief. Atopic eczema treatment should more than any other disease be guided by an individualized approach taking not only the phenotype and genotype of the disease but also psychosocial and gender aspects into account. Significant gains have been made in our understanding of atopic eczema, especially recent insights into genetic and immunologic mechanisms, but still, there is no single treatment to date that has proven to be the quantum leap for atopic patients. Novel treatments have been developed and trialled, however, more studies on novel therapies such as biologicals addressing efficacy, optimum dose and duration of treatment and the target phenotype are urgently needed. Hopefully, the tremendous progress in basic research in the last years will provide new targets for prevention and treatment in the future.

In humans, prolonged sunlight exposure is associated with various pathological states. The continuing drive to develop improved skin protection involves not only approaches to reduce DNA damage by solar ultraviolet B (UVB) but also the development of methodologies to provide protection against ultraviolet A (UVA), the oxidising component of sunlight. Furthermore identification of specific cellular events following ultraviolet (UV) irradiation is likely to provide clues as to the mechanism of the development of resulting pathologies and therefore strategies for protection. Our discovery that UVA radiation, leads to an immediate measurable increase in ‘labile’ iron in human skin fibroblasts and keratinocytes provides a new insight into UVA-induced skin damage, since iron is a catalyst of biological oxidations. The main purpose of this overview is to bring together some of the new findings related to mechanisms underlying UVA-induced iron release and to discuss novel approaches based on the use of multiantioxidants and light-activated caged-iron chelators for efficient protection of skin cells against UVA-induced iron damage.

Extracellular cytokine function of the non-histone nuclear protein high-mobility group box 1 (HMGB1) has recently been recognized as an important drug target for novel anti-inflammatory therapeutics. Accumulating evidence supports the mechanistic involvement of the alarmin HMGB1 in skin response to microbial infection and ultraviolet-induced solar damage. Moreover, HMGB1 modulation of inflammatory signaling and tissue remodeling is now emerging as a causative factor in wound repair, autoimmune dysregulation, and skin carcinogenesis, representing cutaneous pathologies that affect large patient populations with unmet therapeutic needs. Recent structure-based drug discovery efforts have aimed at increasing the number of small molecule- and biologics-based prototype therapeutics targeting HMGB1. Small molecule drugs that may provide therapeutic benefit through HMGB1-directed mechanisms involve HMGB1 inhibitory ligands, Toll-like receptor antagonists, RAGE antagonists, α7 nicotinic acetylcholine receptor agonists, G2A antagonists, serine protease inhibitors, and α-dicarbonyl-based soft electrophiles. Using some of these agents, pharmacological modulation of HMGB1-associated cutaneous pathology has been achieved with an acceptable toxicity profile, and preclinical proof-of-concept experimentation has demonstrated feasibility of developing HMGB1-modulators into novel systemic and topical therapeutics that target cutaneous inflammatory dysregulation.

During the lifetime, our cells encounter many challenges to their own existence. The survival of organisms and cells depends on the interplay within a complex, yet precisely orchestrated network of proteins. Since the discovery of the Rel/NF-κB family of transcription factors, the research has never come to a stop. These proteins are best known for their key roles played in normal immune and inflammatory responses, also in the control of cellular proliferation, differentiation, apoptosis and oncogenesis. The recent years have witnessed an emerging research regarding NF-κB signalling pathways in aging and senescence as well. In this review we go deeply through NF-κB activity in the modern biogerontology, with the arguments around its possible roles in aging. Nevertheless, a detailed molecular action and mechanism of NF-κB regulation during senescence has yet to be determined. Elucidation of the exact role of NF-κB in aging will be crucial for developing new therapeutic strategies.

Cytochromes P450 are members of a superfamily of hemoproteins that catalyze a variety of oxidative reactions in the metabolism of endogenous and exogenous hydrophobic substrates. Fifty-eight cytochrome P450 (CYP) isoenzymes belonging to 18 families have been identified in human cells; the corresponding genes are highly polymorphic, and genetic variability underlies interindividual differences in drug response. The polymorphisms of CYP2D6 significantly affect the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The number of functional CYP2D6 alleles per genome determines the existence of four different phenotypes, i.e. poor, intermediate, extensive, and ultrarapid metabolizers. CYP2D6 genetic variants include copy number variations, single nucleotide substitutions, frameshift and insertion/deletion mutations. This review reports some of the different methodological approaches used to screen for CYP2D6 variants and focuses on methods that have improved variation detection, from conventional techniques to more recent microarray technology and high throughput DNA sequencing. In addition, this review reports some results on clinical relevance of CYP2D6 polymorphisms and provides examples of variability in drug response associated with interindividual phenotypic differences.