Current Drug Targets - Inflammation & Allergy - Volume 2, Issue 1, 2003

Many autoimmune disorders share two common features, dysregulation of the immune system and stress pathways. Two stress pathways, the hypothalamic-pituitaryadrenal (HPA) axis and the sympathetic nervous system (SNS), regulate immune system responses, through release of corticosteroids and norepinephrine (NE), respectively. These neuromediators act on immune cells via specific receptors on their surface to modulate the production of key regulatory cytokines. Glucocorticoids modulate immune responses by glucocorticoid binding to cytoplasmic glucocorticoid receptors within target cells. NE regulates immune responses through interaction with plasma membrane ß- or α-adrenergic receptors (AR). Both NE and glucocorticoids promote humoral immunity by altering macrophages and T cell cytokine production after an antigen challenge. Glucocorticoids and NE do this by inhibiting interleukin (IL)-12, and interferon (IFN)-γ, which drives cell-mediated immunity. Additionally, catecholamines drive humoral immunity by stimulating macrophage IL-10 production. These catecholamine effects are mediated largely via ß2-AR activation. Both glucocorticoids and NE inhibit inflammation. However, under some circumstances NE promotes inflammation through interaction with macrophage α1-AR and subsequent increases in tumor necrosis factor α (TNFα) production. Although macrophages do not normally express α1-AR, expression of this receptor on macrophages and monocytes occurs in some disease states, including rheumatoid arthritis (RA). Through these mechanisms the HPA axis and the SNS influence the course and progression of RA. Thus, the HPA axis and the SNS are likely to play key roles in the pathology of RA. Furthermore, therapeutic agents targeting the neural pathways that normally regulate immune system homeostasis may prove beneficial for treating RA and other autoimmune diseases.

Over the last decades the prevalence of allergic disorders, such as hayfever and asthma has increased worldwide, mostly in westernised countries where up to 20 % of the population are affected. The “hygiene hypothesis” suggests that modernised lifestyles such as improved housing conditions, altered dietary habits and smaller family sizes may be responsible for the decrease in infectious and the increase in allergic diseases. Childhood atopic diseases, like eczema, food allergies and recurrent wheezy bronchitis represent a considerable health problem and a major socioeconomic burden due to the chronicity of these disorders. In recent years, a better understanding of the immunopathogenesis of allergic diseases has evolved, which has contributed to the development of novel more targeted forms of therapy.Allergen injection immunotherapy is the only treatment in current use with the potential for modifying the course of allergic disease. In order to better target mucosal allergies, new approaches of administering allergen, via the sublingual or intranasal route, are being developed. The use of modified allergens, allergen peptides, DNA immunization and the use of novel adjuvants represent alternatives to conventional immunotherapy with potential for improved efficacy with less side effects. For atopic asthma, novel treatment strategies aim at locally targeting inflammed airways. Nebulized monoclonal blocking antibodies and soluble interleukin receptors against “Th2-type” cytokines have been designed. An alternative approach has been the administration of “Th1 -type” cytokines. Although, immunomodulatory strategies provide a promising outlook for the treatment of allergic patients, more studies are needed in the future to address issues of efficacy, safety and long-term effects of altered immune responses.

Leukotrienes (LTs) producing capacity was investigated in calcium ionophore A23187-stimulated peripheral white blood cells and peritoneal inflammatory cells suspension isolated from the same rat. A reverse phase high performance liquid chromatography technique and computerized UV spectroscopy were employed to isolate and quantitate the released LTs namely, LTC4 and LTB4. Preincubation of rat peritoneal inflammatory cells at 37°C for 5 min followed by calcium ionophore A23187 stimulation for another 5 min produced significantly elevated amounts of LTB4 as compared to peripheral white blood cells isolated from the same rat (103+12.7 versus 40+3.6 pmol / 10 7 cells, respectively, mean+SEM). Enhanced generation of LTB4 was associated with production of similar amounts of LTC4 as compared with LTC4 produced by peripheral white blood cells (15.2+4.2 versus 14.6+2 pmol / 107 cells, respectively). In subsequent experiments, when peritoneal inflammatory cells and white blood cells suspension isolated from the same rats were stimulated with calcium ionophore A23187 (1 μM) after preincubation with different concentrations of exogenous arachidonic acid (1, 3 and 10 μM), significantly higher amounts of LTB4 were produced by the peritoneal inflamed cells while a similar amounts of LTC4 were produced by both types of cells. Increased LTB4 formation by rat peritoneal inflammatory cells may prove to be of pathophysiological relevance, since this compound has been described to play an important role in acute inflammatory reaction.

Atopic disorders include a range of conditions such as allergic asthma, -rhinitis, -conjunctivitis, -dermatitis, food and drug allergies and anaphylaxis. Induction of T helper (Th)-2 immune response with consequent IgE dependent eosinophil, basophil and mast cell mediated tissue damage is the characteristic feature of allergies. The mechanism underlying this unique and long appreciated feature of allergy is being elucidated at the molecular level with advances in our knowledge of the chemokine system. Thus, chemokines that target CCR3 in concert with Th2 cytokines appear to play a pathogenic role in allergy. In contrast, chemokines that target CXCR3 in concert with Th1 cytokine appear to play a beneficial role. Accordingly, inhibiting CCR3 / Th2 pathway using CCR3 antagonists is viewed as a potentially useful strategy for anti-allergy drug development. In contrast, the idea of using CXCR3 agonists to inhibiting allergic response by promoting CXCR3 / Th1 pathway faces serious concerns of their potential pro-inflammatory activities in vivo. In this article we have critically evaluated the literature examining the principle and potential of this anti-allergy drug development strategy including a summary of various compounds that are under investigation.

Among the numerous genes controlled by cyclic adenosine monophosphate (cAMP) / protein kinase A signalling machinery is the gene encoding the inducible nitric oxide synthase (iNOS), an enzyme catalyzing the synthesis of a highly reactive free radical nitric oxide (NO). While being a major microbicidal and tumoricidal molecule, iNOS-derived NO has also been implicated in tissue destruction, as well as in regulation of inflammatory / immune cell function in various disorders associated with excessive inflammation. A feasible way for cAMP-dependent therapeutic control of inflammation, including iNOS-mediated NO synthesis, could involve the administration of drugs that block the enzymatic activity of cAMP-degrading phosphodiesterases (PDE). Indeed, cAMP-elevating PDE inhibitors can influence iNOS activation in different cell types in vitro, and their potent anti-inflammatory effects in experimental disease models and clinical studies were frequently accompanied with profound modulation of NO production. A set of conflicting data has been generated over the years, ranging from strong suppression to marked enhancement of NO release by cAMP-increasing PDE inhibitors, depending on celltype, iNOS stimuli, and / or the agents used. The present review summarizes the data on iNOS modulation by cAMP-elevating PDE inhibitors and possible mechanisms behind it, speculating on its contribution to the therapeutic effects of these drugs.

Background: Cast metal posts-and-core are frequently used to retain restorations to extensively destroyed teeth. However, the influence of different cements on the posts bond strength to dentin remains unclear. Objective: to evaluate the effect of different cements on the bond strength of cast metal posts and dentin.

Methods: Forty roots (14 mm length) of extracted human teeth were endodontically treated and prepared. Impressions of each root canal were taken to obtain customized cast metal posts. The roots were randomly divided into 4 groups (n=10): (1) ZP: zinc phosphate cement (non adhesive); (2) ARC_Sin: Single Bond adhesive and RelyX ARC; (3) ARC_Sco: Scotchbond adhesive and RelyX ARC; (4) U200: RelyX U200. After cementation, the samples were cross-sectioned to obtain specimens of 1mm thickness. Push-out test was performed applying a compressive load (0.5 mm/min) to the center of the metal post until failure. Bond strength was calculated based on the diameter of the root canal and the thickness of each specimen. Data were analyzed using ANOVA and Tukey (α=0.05). The fracture mode was analyzed.

Results: Bond strength values were statistically similar between the groups (p>0.05). The fracture analysis showed the prevalence of mixed fractures (cement partially attached to the dentin and/or post). Experimental groups showed inexpressive amount of adhesive fractures (complete detachment of the cement from dentin and/or post). The ARC_Sco and U200 groups presented higher prevalence of dentin cohesive fracture.

Conclusion: Bonding had no influence on the immediate bond strength between cast metal posts and root canal dentin.

Cell migration is mediated by a group of chemotactic cytokines called chemokines: low molecular weight molecules that have been shown as important leukocyte chemical attractants to sites of inflammation and infection.Eotaxin-1, also called CCL11, was first described in 1994, as a highly specific eosino-phils chemokine. Many cell types including lymphocytes, macrophages, bronchial smooth muscle cells, endothelial cells and eosinophils, are able to produce this chemokine, predominantly after cytokine stimulation, however little is known about its expression in human skin in vivo.Eotaxin-1 also regulates the chemiotaxis and, in some conditions, activation of basophils, mast cells and T lymphocytes.Chemokine receptors are named from their ligand families, thus the CC chemokine eotaxin-1 binds to the CCR3 receptor which is expressed on eosinophis, mast cells, Th2 type lymphocytes and even on keratinocytes. It seems that eotaxin-1 is one of the most important cytokines involved in tissue inflammation playing a central role in the pathogenesis of allergic airway diseases (asthma and rhinitis), in inflammatory bowel disease and gastrointestinal allergic hypersensitivity and recently it has been proposed as a therapeutical target for these conditions. Our group has studied the role of eotaxin-1 in the pathogenesis of two skin conditions: dermatitis herpetiformis and AIDS-associated eosinophilic folliculitis, demonstrating that this chemokine, together with Th2 type cytokines (IL-13 and IL-4) is important in cell recruitment, inflammation and tissue damage; moreover eotaxin has proven to paly an important role in other skin conditions such as, bullous pemphigoid, pemphigoid gestationis, atopic dermatitis and allergic drug reactions Recent advances in the understanding of eotaxin-1-mediated mechanisms of chemotaxis in allergic and inflammatory conditions may predict that therapeutic antagonism is achievable. This paper will focus on the role that eotaxin and its receptor play in the pathogenetical mechanism in a number of dermatologic diseases, some of which, like atopic dermatitis, may benefit from the introduction of novel and more selective therapeutic options.