Barbara Rogala

Platelet-Activating Factor (PAF): A Review of its Role in Asthma and Clinical Efficacy of PAF Antagonists in the Disease Therapy

PAF is a potent proinflammatory mediator which plays a role in different inflammatory diseases, including bronchial asthma. PAF is able to induce key pathogenic features of asthma and to influence the activity of cells involved in immune-inflammatory process; it may therefore serve as a possible direct target for anti-asthmatic drugs. Specific PAF antagonists (PAF receptors antagonists and recombinant plasma PAF acetylhydrolase attenuating its bioactivity) contributed to our better understanding of its role in asthma but unfortunately have not provided any further therapeutic option in the disease, due to minor or lacking effects. However, single treatment with PAF antagonist in asthma therapy revealed at its very best only a little effect. The concept of combined therapy targeting PAF and other mediators involved in the disease seems to be of particular interest. This review is a brief summary of relevant scientific basis as well as clinical research on the role of PAF in asthma, the significance of anti-PAF therapy in the disease, as well as US. patents (1998-2002) related to PAF antagonists.

Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma

Platelet activating factor (PAF) is a potent phospholipid mediator involved in anaphylaxis and chronic inflammatory disorders, including bronchial asthma. PAF is able to act both, directly as a chemotactic factor and indirectly through the release of other inflammatory agents. Apart from its known potent ability to activate platelets, PAF influences other immune and inflammatory cells function involved in asthma, which may be of importance in the pathogenesis of the disease. In addition, PAF administration can mimic some of abnormalities observed in asthma, including bronchoconstriction, bronchial hyper responsiveness, and gas exchange impairment, which may be mediated by leukotrienes acting as secondary mediators of some PAF effects. Therefore, there has been an extensive interest in the role of PAF in human asthma and major efforts have been continued to discover drugs acting thorough inhibition of PAF effects in the disease. Surprisingly, PAF receptor antagonists have not clearly proven their clinical benefits. It may appear that the combined blockage of PAF effects and other mediators involved in asthma is a way to improve clinical efficacy and also an interesting approach to control inflammation in the disease. This review will focus on two main issues: the role of PAF and PAF antagonists in asthma.

Platelet function in cutaneous diseases

Blood platelets participate actively in immune-inflammatory processes. Responding to the variety of stimuli such as cell activation leads to the release of several mediators, including RANTES, platelet factor 4, beta-thromboglobulin, thymus and activation-regulated chemokine (TARC/CCL17), serotonin and arachidonic acid metabolites. It also affects the expression of immunomodulatory and adhesive molecules, including CD154 and P-selectin. Immune–inflammatory processes associated with skin diseases could induce platelet activation, which, in turn, would contribute to acceleration and modulation of these processes. Activated platelets are capable of facilitating leukocyte rolling in the skin and the release of skin inflammation mediators. Changes in platelet function and behaviour may occur in certain types of skin inflammatory conditions and platelets might then be an important effector cell of the skin immune system, contributing to the pathogenesis of some skin inflammatory disorders. The changes in platelet activity and reactivity have been demonstrated to show distinctly different pathogenic mechanisms in cutaneous diseases, such as urticaria, atopic eczema/dermatitis syndrome and psoriasis. Considering the risk of cardiovascular events, some of them seem to be of clinical significance. This contribution is a brief outline of the present knowledge of the platelet function in dermal disorders.

Sex hormones and urticaria

Chronic urticaria is characterized by mast cells/basophils activation which initiate the inflammatory response. Pathogenetically, the disease may in many cases represent an autoimmune phenomenon. Altered function of the neuro-endocrine-immune system due to stress and other factors has also been implicated its pathogenesis. Sex hormones modulate immune and inflammatory cell functions, including mast cell secretion, and are regarded as responsible for gender and menstrual cycle phase-associated differential susceptibility and severity of some autoimmune and inflammatory diseases. Chronic urticaria is approximately twice more frequent in women than in men. In addition, urticaria may be associated with some diseases and conditions characterized by hormonal changes, including endocrinopathy, menstrual cycle, pregnancy, menopause and hormonal contraceptives or hormone replacement therapy. Hypersensitivity reactions to endogenous or exogenous female sex hormones have been implicated in the pathogenesis of urticarial lesions associated with estrogen and autoimmune progesterone dermatitis. We observed lower serum dehydroepiandrosterone sulfate (DHEA-S) concentration in patients with chronic urticaria with positive and negative response to autologous serum skin test. Thus, the influence of fluctuations in the hormonal milieu and altered sex hormone expression on the triggering-off, maintenance or aggravation of urticaria should be taken into account. In addition, the possible impact of estrogen mimetics, in the environment and in food, on the development of disease associated with mast cell activation must be considered. This review endeavours to outline what is known about the possible influence of sex hormones in the expression of urticaria.

Decline in dehydroepiandrosterone sulfate observed in chronic urticaria is associated with psychological distress.

Objective: Dehydroepiandrosterone sulfate (DHEA-S) decline in chronic urticaria (CU) may be involved in etiopathogenesis of the disease or is a secondary phenomenon resulting e.g. from psychological distress. The relation between mental stress and skin diseases is well documented, however not focused on urticaria. We sought to explore the association of mood disturbances and the sense of coherence (SOC), as psychological distress parameters, and DHEA-S decline in patients suffering from CU. Methods: The patient sample included 54 subjects with active CU. Fifty-nine healthy subjects were enrolled in the control group. In all subjects DHEA-S serum concentration was measured and mental status analyzed using the State and Trait Anxiety Inventory, SOC Questionnaire and Beck Depression Inventory. Results: Urticaria patients showed lower serum concentration of DHEA-S (p = .01) and lower level of the SOC (p = .009), as well as higher level of anxiety as a state (p < .001) and as a trait (p = .001), and higher level of depression (p = .003). DHEA-S concentration correlated negatively with the level of anxiety as a trait (p = .02) and the level of depression (p = .046), and positively with the SOC level (p = .03). Conclusions: The results of the present study show that CU patients suffer from the psychological distress. We demonstrated for the first time that DHEA-S decline observed in CU patients might be a phenomenon secondary to psychological disturbances. ASST = autologous serum skin test; BDI = Beck Depression Inventory; CU = chronic urticaria; D = level of depression; DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate; SOC = sense of coherence; SOC-29 = Sense of Coherence Questionnaire; STAI = State-Trait Anxiety Inventory; X1 = level of anxiety as a state; X2 = level of anxiety as a trait.

Platelet Activation During Allergic Inflammation

Blood platelets, apart from their traditional and well-recognised function in haemostasis, play an essential and active role in allergic inflammation e.g. through their participation in cell recruitment from blood to site of immune reactivity as a result of direct interactions with leukocytes, and through the release of inflammatory mediators. Platelet activation may occur during human allergic reactions both systemically and locally at the site of allergic inflammation as a result of an IgE-dependent process and as a secondary event caused by other inflammatory or immune stimuli. Altered platelet function as measured by platelet secretion, expression of surface molecules, aggregation, adhesion or arachidonic acid metabolism has been found in patients suffering from allergic diseases. These blood elements have been implicated in the pathogenesis of allergic diseases associated with the so-called atopic diathesis. This paper reviews the platelet activity and reactivity in allergic inflammation, along with our own findings concerning platelet release reaction and the phenomenon of platelet aggregation in patients with different clinical forms of allergy.

Enhanced platelet activation in patients with atopic eczema/dermatitis syndrome.

Data gathered prove that circulating platelets are activated upon human allergic inflammation, partly as a result of direct IgE-mediated process. It has been indicated that platelets may contribute to pathogenesis of atopic eczema/dermatitis syndrome (AEDS). Authors of the recent study have investigated systemic platelet activation in patients with AEDS on the basis of blood level of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4), which are recognized markers of platelet activation, also belonging to C-X-C chemokine family. Plasma levels of beta-TG and PF4 were measured by enzyme-linked immunoassay (ELISA) in 18 AEDS patients with moderate disease activity and 23 healthy, nonatopic individuals. No differences in peripheral platelet count of the two groups were noted. Only four (33.3%) AEDS patients represented beta-TG and PF4 within the control range; plasma beta-TG and PF4 were significantly increased (p < 0.001) in the AEDS group compared as a whole with the control subjects. No association between circulating concentrations of beta-TG or PF4 and total IgE levels in AEDS patients was proved. The results suggest that some patients with AEDS may have enhanced blood platelet activity as expressed by beta-TG and PF4 level.

Assessment of platelet activity as expressed by plasma levels of platelet factor 4 and β‐thromboglobulin in patients with chronic idiopathic urticaria

Abstract:  Blood platelet significance in inflammation is recognized but poorly characterized in urticaria. It is known that platelets are activated during inflammatory processes and are involved in modulating inflammatory and immune response via various mediator release. The aim of our study was to investigate the functional state of platelets, expressed by release reaction of C‐X‐C chemokines such as platelet factor 4 (PF‐4) and β‐thromboglobulin (β‐TG) in chronic idiopathic urticaria (CIU). Plasma levels of PF‐4 and β‐TG, which are established markers of in vivo platelet activation and which play important role in inflammatory processes, were measured by enzyme‐linked immunosorbent assay in 19 patients with CIU and in 25 healthy subjects. Mean plasma PF‐4 level in CIU patients and control subjects was 5.01 ± 1.67 and 4.13 ± 2.05 IU/ml, respectively, whereas that for β‐TG was 29.3 ± 14.0 and 25.2 ± 12.6 IU/ml, respectively. In our small study, there have been no significant differences found between the members of the control and CIU group regarding plasma levels of PF‐4 and β‐TG. Further studies should be performed to elucidate whether any systemic platelet activation occurs in CIU.

The Role of Interleukin-33 in Rhinitis

IL-33, a member of the IL-1 cytokine family and a ligand to receptor ST2, has great potential to induce a T helper 2-type inflammatory response. IL-33 is proven to be released by epithelial cells during their injury by different environmental stimuli such as airborne allergens, viruses, and air pollutants. IL-33 acting as an endogenous danger signal is termed an alarmin. As such, this cytokine is considered to play a crucial role in an allergic inflammatory disease such as rhinitis. Recent investigations regarding the IL-33/ST2 axis involvement in Th2 inflammatory response and pathogenesis of rhinitis have been reviewed. The role of IL-33 as a novel promising therapeutic target has also been discussed.

Anaphylactoid reaction after the use of sodium tetradecyl sulfate: a case report.

Sodium tetradecyl sulfate is a sclerosing agent that has been widely used to treat varicose veins of the legs and digestive tract. Despite the multitude of side-effects of sclerotherapy procedures and sclerosing-drug administration, the medical literature reports only on a few cases of life-threatening hypersensitivity reactions resulting from sodium tetradecyl sulfate therapy. A case is reported of a 49-year-old woman who developed anaphylactoid reaction after the administration of the Fibro-vein for varicose veins in the legs. Attention is drawn to this adverse event and underlines the necessity for potential hypersensitivity assessment before the drug application.