Current Pharmaceutical Design - Volume 16, Issue 32, 2010

The rationale for promoting a multidisciplinary update on glucocorticoids can be identified from one side in the growing evidence of the role of inflammation in the pathogenic mechanism of many diseases, and from the other in the physiologic control upon the regulators of tissue functions that, in addition to their anti-inflammatory action, these hormones exert. When we think of inflammation our mind goes back to the five historical signs: rubor, calor, dolor, tumor and functio laesa: however it appears today that those signs represent late features of the pathologic process, while the role of their mediators is subverted much earlier in the development of different diseases. Indeed, it is known that such mediators, before being responsible for inflammatory changes, regulate important functions, among which cell social behavior, angiogenesis, haemostasis, smooth muscle contraction, and many others upon which our physiologic wellbeing depends. As to such subtle progressive subversions, it appears of key interest today that certain critical genes polymorphisms may be responsible for some harmful inflammatory responses. For instance, they are reported to increase the risk of preterm birth and of related maternal-foetal diseases, while the incidence of such complications is decreased by those polymorphisms addressing the maternal immune response against inflammation [1]. The association with gene polymorphisms has also been reported to increase the risk of developing asthma and chronic obstructive pulmonary disease, and their role is considered crucial for the development of new strategies for lung disease management [2-4]. Indeed, these observations suggest that high risk populations could benefit from compounds such as glucocorticoids, able to rebalance the inflammatory response mediators towards physiologic homeostasis. However, differing from other hormones widely introduced in medical practice, the use of glucocorticoids is generally restricted to treating advanced pathologic conditions. Furthermore, one relevant matter is that, in the majority of the situations for which they are used, essaying the circulating glucocorticoid concentration is devoid of therapeutic information, and therefore it is of no help in the management of the disease. This suggests that the main features of hormonal involvement in pathologic processes may occur at a tissue level, and therefore that at such level they should be searched for. For instance, some cases of recurrent abortion are characterized by an increased number of decidual natural killer cells (NK), with no other clinical evidence than pregnancy loss. These cases have been shown to benefit from glucocorticoid treatment, bringing NK concentration back to normal values, and favoring a positive outcome of gestation [5,6]. These observations suggest that the clinical use of glucocorticoids can be approached looking at them as natural regulators of functions, rather than dangerous drugs to be avoided. Such point of view reflects the opinion that early changes in the balance of the mediators of cellular functions represent the cause of a pathology gradually evolving towards inflammation, rather than its mere consequence.

Glucocorticoids (GCs) constitute the most important and widely prescribed class of anti-inflammatory and immunosuppressive drugs. Since their first clinical use more than half a century ago, they have been employed for therapeutic treatment in a variety of diseases such as atopic disorders, autoimmune diseases and cancer. Their efficacy is related to their capability to reduce the expression and activity of many pro-inflammatory agents, that is named “transrepression”. Unfortunately, they also induce serious adverse effects, in particular upon high dosage and prolonged usage, many of which are due to the transcription of genes involved in metabolic processes, that is called “transactivation”. This discrepancy is the driving force for discovery of novel safer GC receptor ligands, such as selective GCs receptor agonists (SEGRAs) able to induce transrepression, whilst avoiding transactivation. The aim of this review is to give an overview of the above-mentioned mechanisms at the basis of GCs action and to summarize the results obtained with SEGRAs in terms of efficacy versus side effects and discuss the opportunities and challenges that this class of ligands might offer for clinical arena.

Inhaled glucocorticoids, also know as corticosteroids (ICS), revolutionized the treatment of asthma by suppressing airways inflammation and ICS therapy now forms the basis of treatment of asthma of all severities. More recently and usually in combination with a long-acting β-agonist (LABA), ICS use has been established in the treatment of chronic obstructive pulmonary disease (COPD). In asthma, ICS improves asthma control, lung function and prevents exacerbations, including hospital admissions and probably decreases mortality. Similar effects are seen in COPD but to a much lesser degree, however, an improvement in symptoms such as breathlessness and reduction in exacerbations occur particularly in more advanced disease with ICS. Chronic inflammation is a feature of both asthma and COPD, although there are differences in the site and characteristics of the inflammatory response. ICS have proven to be less effective in patients with severe asthma, smoking asthmatics and in patients with COPD. ICS act by binding to and activating specific cytosolic receptors (GR), which then translocate to the nucleus where they regulate gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. GR is able to selective repress specific inflammatory genes by differing actions on specific intracellular signalling pathways and transcription factors such as nuclear factor κB and on kinases pathways. Abnormal activation of these pathways may result in glucocorticoid resistance. Although, ICS/LABA combinations will remain the main focus of treatment of airways diseases in the near future; other combinations that improve the efficacy of ICS by reducing the abnormal activation of pathways that cause glucocorticoid resistance will be developed.

Glucocorticoids (GC) are drugs commonly used, by approximately 1% of the total adult population as anti-inflammatory and immunosuppressive therapies for asthma, inflammatory bowel disease, dermatological, ophthalmic, neurological, and rheumatic autoimmune diseases. Supporting evidence exists of GC use in both immune mediated and non-immune mediated heart disease. The molecular mechanisms by which GC induces immune-modulation and direct cardioprotection, are complex and not fully understood. We review herein, the current knowledge of GC use in various immune-mediated or non-immune mediated cardiovascular conditions. GC have been investigated in autoimmune, inflammatory and idiopathic heart diseases such as atrio-ventricular conduction abnormalities, rheumatic fever, myocarditis, dilated cardiomyopathy, Churg-Strauss syndrome, Kawasaki disease and sarcoidosis. GC therapy has been studied in non-autoimmune and non-inflammatory indications such as acute myocardial infarction, angina, postpericardiotomy syndrome and other pericardial diseases, endocarditis and cardiac amyloidosis, as well as in invasive cardiology, coronary interventions, and cardiopulmonary- bypass surgery. Despite GC's role as natural, physiologic regulators of the immune system, cardiovascular adverse outcomes may occur. Some of the well-known side effects of GC therapy involve bone, metabolic, and cardiovascular systems and include osteoporosis, fractures, dyslipidemia, diabetes, obesity, and hypertension.

Glucocorticoid Receptors (GRs) have been identified in all bone cells. The molecular structure of human GR is organized into 3 major functional domains: the N-terminal immunogenic domain, the central DNA-binding domain and the C-terminal ligand-binding domain. Human GR is a product of a gene composed of 10 exons, located in the chromosome 5q31-32. An alternative splicing in exon 9 gives rise to 2 mRNAs encoding the classical hGRα and hGRβ isoforms. Human GRα is present in the cytoplasm of almost all cells, as a multiprotein complex and works as a ligand-dependent transcription factor. In contrast to hGRα, hGRβ is located in the nucleus, does not bind hormone or activate glucocorticoid (GC)-response genes. It works as a dominant negative inhibitor of hGRα. The effects of GCs are - at least in part - mediated via specific GRs (genomic effect), however GCs also have acute non genomic effects. Osteoblasts are the most obvious target of GCs in bone, suppressing their maturation, activity and survival. Osteoblasts stimulate osteoclastic activity through the RANKL-osteoprotegerin-RANK system, but this effect is weaned off rapidly by the incoming suppression of the global osteoblast activity. The direct action of GCs on osteoclasts results almost invariably in a suppression of cell activity. When exposed to high concentrations of GCs, osteocytes undergo a slow process of apoptosis. Osteocytes with their dendritic network sense the skeletal strain and stress of normal daily activities. This continuous stimulus prevents the production of sclerostin and possibly DKK1, which are able to strongly suppress osteoblast formation by interacting with the Wnt system. GCs are thought to stimulate sclerostin secretion from osteocytes.

Glucocorticoids play an essential role in embryonic development and tissue homeostasis and possess important antiinflammatory and immunosuppressive properties. Due to their very wide spectrum of activity, glucocorticoids are one of the most commonly used drugs-used in the treatment of asthma, arthritis, autoimmune diseases and shock/SIRS. Glucocorticoids are a main component of treatment regimens in hematological malignancies due to their pro-apoptotic properties and are also used as co-treatment several other cancers and chemotherapy regimens including those in breast cancer treatment. In breast cancer, however, glucocorticoids may have diverse effects and could inhibit chemosensitivity. Additionally, glucocorticoids through their receptor may interact with ER in a feedback loop regulating each other's activities. The normal variation of glucocorticoid levels with time of the day, menstrual cycle or year could have a interesting chronobiological interaction with the well recorded variation in breast cancer proliferation and metastatic potential. Glucocorticoids could play a very complex role in breast cancer epidemiology, biology and treatment; this review aims to present a comprehensive discussion as well as speculate future directions for research.

The story of cytokines in pregnancy began about 30 years ago, approximately in concomitance with the understanding that cytokines are autocrine-paracrine regulators of physiological processes. Pro-inflammatory cytokines are predominant in the early and late events of gestation, e.g. pregnancy establishment and parturition, both of which have been described as inflammatory-like events. Proinflammatory cytokines are also produced in response to microbes constantly in contact with the female reproductive tract. While a proinflammatory response is beneficial to successful pregnancy, an exaggerated response, as may occur for an unresolved infection, could result in an unfavorable pregnancy outcome in animals and humans. Therapeutic strategies are required to avoid the risks to the health of fetus and mother. In this review, we discuss the involvement of pro-inflammatory cytokines in pregnancy at implantation and parturition, including the pathologies which might be related to an alteration of the cytokine levels. We also deal with the use of anti-cytokines and/or anti-inflammatory mediators to antagonize the action of pro-inflammatory cytokines. Finally we discuss the potential of animal models to evaluate the association of cytokines in the establishment and maintenance of pregnancy.

For many years glucocorticoids have been used world-wide in pregnant women for treatment of a variety of medical disorders, from bronchial asthma to systemic lupus erythematosous, to renal transplant. More recently their administration has been successfully addressed to the prevention of congenital fetal diseases. In some of these, such as for instance the 21-hydroxylase deficiency leading to congenital adrenal hyperplasia, the pathogenic mechanism is well known, while in others, such as the cystic adenomatoid malformation of the lung, it is not yet understood. Besides these types of diseases, there are acquired inflammatory conditions impairing the physiologic evolution of pregnancy that benefit from glucocorticoid administration. This is the case in recurrent miscarriage due to increased concentration of decidual Natural Killer cells, as well as in the Romero's syndrome, leading to premature parturition and related life threatening fetal complications. However, in spite of its prominent efficacy, the therapy is generally viewed with some suspicion because of possible fetal and maternal adverse effects. With the aim to contribute to a better knowledge of the basic mechanisms of glucocorticoid protection, we reviewed the regulation of their trans-placental passage, their biological effects on gestational environment, their possible ‘programming’ and teratogenic action, and their accepted use for prevention and cure of pregnancy complications. We believe that a more qualified and liberal use of these compounds will lead in many cases to a significant improvement of fetal and maternal prognosis.