Zenon Brzoza

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.

Adaptation and initial results of the Polish version of the GA2LEN Chronic Urticaria Quality Of Life Questionnaire (CU-Q2oL)

BACKGROUND Strong negative influence upon the quality of life in chronic urticaria is well proved. Before the GA(2)LEN Chronic Urticaria Quality of Life Questionnaire (CU-Q(2)oL) was introduced, the quality of life in chronic urticaria had been measured with general or dermatology specific questionnaires. CU-Q(2)oL was initially developed in Italy and consisted of 23 items divided into 6 quality of life dimensions. OBJECTIVE The aim of our study was to adapt the Polish version of CU-Q(2)oL and to provide initial results from the Polish sample. METHODS To prepare the Polish version forward and back translation was prepared. After cognitive debriefing, we collected a group of 126 chronic urticaria patients who completed Polish CU-Q(2)oL, Dermatology Life Quality Index (DLQI) and Skindex-29 questionnaire. Disease severity was assessed with Urticaria Activity Score (UAS). We performed the factorial analysis to identify CU-Q(2)oL subscales in our study, internal consistency and convergent validity assessment as well as factors driving the results. Moreover, we analysed tools reproducibility and responsiveness. RESULTS The factor analysis resulted in six subscales of Polish CU-Q(2)oL version with satisfying face validity: Itching, Swelling/Mental status, Functioning, Sleep, Eating/Limits, Embarrassment. All subscales presented recommended internal consistency and convergent validity. Disease severity was the only factor predicting results of all the subscales. Polish CU-Q(2)oL version was reproducible and sensitive to change. We noticed the highest quality of life impairment in Itching and Embarrassment subscales whereas Eating/Limits was the least affected. CONCLUSIONS Our study supports reliability, responsiveness and validity of the Polish version of CU-Q(2)oL - easy in use, non time-consuming instrument to be used in research, clinical management and treatment outcome assessment and is one more step to confirm quality of life impairment in chronic urticaria.

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.

Increased d‐dimer concentration in plasma of patients with severe acute urticaria

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Increased concentration of platelet-derived chemokines in serum of patients with delayed pressure urticaria

BACKGROUND Delayed pressure urticaria (DPU) is a distinct form of urticaria, characterized by marked dermal swelling, deep inflammatory infiltrate and systemic symptoms. Little is known about inflammatory mediators involved in this disease. OBJECTIVE To investigate secretion of platelet-specific chemokines, platelet factor 4 (PF-4) and beta-thromboglobulin (beta-TG) during the course of DPU. METHODS AND MATERIAL Plasma concentrations of PF-4 and beta-TG were measured in eight adult DPU patients and in 15, age- and sex-matched, healthy controls. RESULTS Plasma PF-4 and beta-TG concentration scores were significantly higher in the DPU group as compared with the control subjects. CONCLUSION The present study, as well as an earlier contribution, suggest that distinct platelet activity may be identified in different types of urticaria. In contrast to chronic idiopathic urticaria, chronic urticaria with a positive response to autologous serum skin testing, and acute urticaria, delayed pressure urticaria may be associated with increased secretion of platelet chemokines, similar to that observed in cold urticaria.

Markers of antioxidant defence system and lipid peroxidation in peripheral blood of female patients with chronic idiopathic urticaria.

Oxidative stress is an important event in lesional skin of patients with chronic idiopathic urticaria (CIU). In the present study, we assessed blood oxidant/antioxidant status of patients suffering from CIU with positive response to autologous serum skin test (ASST) and with negative ASST, to improve our understanding of biological processes and the part of oxidative stress in this disease. Activities of manganese superoxide dismutase (MnSOD), copper–zinc superoxide dismutase (Cu/ZnSOD), glutathione peroxidase (GSH-PX), and catalase (CAT) as indices of enzymatic antioxidant capacity, as well as malondialdehyde (MDA) level as a maker of lipid peroxidation were measured in plasma and erythrocytes from 14 CIU female patients showing positive ASST, 31 CIU female patients with negative ASST and in 19 sex- and age- matched healthy subjects. The antioxidant enzyme activity in plasma and in erythrocytes did not differ significantly among the three groups. Also, the plasma and erythrocytes MDA levels were similar in the three groups. Based on our results, it seems that systemic activity of the enzymatic antioxidants (CuZn/SOD, MnSOD, GSH-Px, and CAT) as well as level of lipid peroxidation determined by MDA may not be increased in the course of immune-inflammatory processes associated with CIU. We also suggest that the systemic oxidant/antioxidant status of CIU patients, showing positive response to ASST, may not be different from that of CIU patients with negative ASST.