Atopic dermatitis: a review of diagnosis and treatment. (9/415)

Atopic dermatitis is a common, potentially debilitating condition that can compromise quality of life. Its most frequent symptom is pruritus. Attempts to relieve the itch by scratching simply worsen the rash, creating a vicious circle. Treatment should be directed at limiting itching, repairing the skin and decreasing inflammation when necessary. Lubricants, antihistamines and topical corticosteroids are the mainstays of therapy. When required, oral corticosteroids can be used. If pruritus does not respond to treatment, other diagnoses, such as bacterial overgrowth or viral infections, should be considered. Treatment options are available for refractory atopic dermatitis, but these measures should be reserved for use in unique situations and typically require consultation with a dermatologist or an allergist.  (+info)

Activation of leukotriene synthesis in human neutrophils by exogenous arachidonic acid: inhibition by adenosine A(2a) receptor agonists and crucial role of autocrine activation by leukotriene B(4). (10/415)

We report here that the apparent inability of isolated human polymorphonuclear leukocytes (PMNs) to efficiently transform arachidonic acid (AA) is the consequence of A(2a) receptor engagement by endogenous adenosine accumulating in incubation media. Indeed, when adenosine is eliminated from PMN suspensions by the addition of adenosine deaminase, or when cells are incubated with adenosine A(2a) receptor antagonists, important quantities (40-80 pmol/10(6) cells) of 5-lipoxygenase products are synthesized by PMN incubated with 1 to 5 microM exogenous AA. The selective A(2a) receptor agonist CGS21680 was a very potent inhibitor of the AA-induced leukotriene (LT) synthesis, showing an IC(50) of approximately 1 nM. The mechanism of AA-induced stimulation of LT synthesis observed in the absence of extracellular adenosine was investigated. In adenosine deaminase-treated PMN, exogenous AA induced Ca(2+) mobilization and the translocation of 5-lipoxygenase to nuclear structures. A time lag of 20 to 60 s (variable between PMN preparations) was observed consistently between the addition of AA and the elevation of intracellular Ca(2+) concentration (and LT synthesis), indicating that AA itself did not trigger the Ca(2+) mobilization in PMN. This AA-induced Ca(2+) mobilization, as well as the corresponding 5-lipoxygenase translocation and stimulation of LT synthesis, was blocked efficiently by the LT synthesis inhibitor MK0591, the LTB(4) receptor antagonists CP105696 and LY223982, and the LTA(4) hydrolase inhibitor SC57461A. These data demonstrate that AA is a highly potent and effective activator of LT synthesis and acts through a mechanism that requires an autocrine stimulatory loop by LTB(4).  (+info)

Repeated antigen inhalations alter chemical mediators that cause asthmatic obstruction in guinea pigs. (11/415)

The contributions of histamine, cysteinyl leukotrienes (CysLTs) and thromboxane A2 (TXA2) to the asthmatic responses and the magnitudes of blood and lung eosinophilia at acute and chronic stages of our asthmatic model were comparatively determined. Guinea pigs were alternately sensitized/challenged by inhalation with ovalbumin+Al(OH)3 and ovalbumin, once every 2 weeks. Effects of mepyramine, pranlukast (a CysLT antagonist) and seratrodast (a TXA2 antagonist) on the early (EAR) and/or the late asthmatic response (LAR) were assessed at the second and fourth antigen challenges. The second challenge caused EAR but not LAR. Although the EAR was decreased at the fourth challenge, a substantial LAR was seen. Both mepyramine and seratrodast inhibited the EAR at the second challenge by approximately 50%. However, at the fourth challenge, these drugs did not inhibit the EAR. The LAR at the fourth challenge was attenuated by pranlukast and seratrodast by 45% and 40%, respectively. Both the blood and lung eosinophilia were modestly and markedly induced 5 h after the second and fourth challenges, respectively. These results strongly suggest that repetition of antigen challenge induces quantitative alterations of chemical mediators participating in the asthmatic responses and a change of the body state under which eosinophils exhibit enhanced migratory activities.  (+info)

Leukotrienes are involved in leukocyte recruitment induced by live Histoplasma capsulatum or by the beta-glucan present in their cell wall. (12/415)

1. The inflammatory cell influx towards the peritoneal cavity in mice inoculated i.p. with live or dead Histoplasma capsulatum or with its subcellular preparations was studied. We also evaluated the effects of dexamethasone (Dexa) or MK886, an inhibitor of leukotriene (LT) biosynthesis, on the recruitment of leukocytes. 2. Live yeast form of fungus (LYH) induced an increase in neutrophils (NE) which was highest 4 to 24 h after inoculation. Mononuclear cell (MN) migration beginning at 24 h with a gradual increase over 48 and 168 h, and an eosinophil (EO) recruitment occurs between 24 and 48 h. 3. NE and EO recruitment induced by dead mycelial form of fungus (DMH) was greater than that observed for dead yeast form of fungus (DYH). A similar leukocyte migration pattern was seen after i.p. injection of the alkali-insoluble fraction (F1) from DYH (F1Y) and F1 from DMH (F1M) this being more active than former. The difference in concentration of beta-glucan in DYH and DMH could explain the different inflammatory capacity exhibited by the two forms of H. capsulatum. 4. LT seems to be the principal mediator of leukocyte migration in response to LYH, DYH or DMH or to beta-glucan. However, other mediators appear to contribute to NE and EO migration since the treatment with Dexa was more effective in inhibiting cell migration than MK886. Complement dependent leukocyte migration may participate in this recruitment. Treatment with MK886 completely abolished MN cell migration, indicating its dependence on the presence of LT.  (+info)

Leukotriene C(4) (LTC(4)) does not share a cellular efflux mechanism with cGMP: characterisation of cGMP transport by uptake to inside-out vesicles from human erythrocytes. (13/415)

The transport of cGMP out of cells is energy requiring and has characteristics compatible with an ATP-energised anion pump. In the present study a model with inside-out vesicles from human erythrocytes was employed for further characterisation of the cGMP transporter. The uptake of leukotriene C(4) (LTC(4)), a substrate for multidrug resistance protein (MRP), was concentration-dependently inhibited by the leukotriene antagonist MK571 (IC(50)=110+/-20 nM), but cGMP was unable to inhibit LTC(4) uptake. Oxidised glutathione (GSSG) and glutathione S-conjugates caused a concentration-dependent inhibition of [(3)H]cGMP uptake with IC(50) of 2200+/-700 microM for GSSG, 410+/-210 microM for S-(p-nitrobenzyl)glutathione and 37+/-16 microM for S-decylglutathione, respectively. Antioxidants such as reduced glutathione and dithiothreitol did not influence transport for concentrations up to 100 microM, but both inhibited cGMP uptake with approx. 25% at 1 mM. The cGMP pump was sensitive to temperature without activity below 20 degrees C. The transport of cGMP was dependent on pH with maximal activity between pH 8.0 and 8.5. Calcium caused a concentration-dependent inhibition with IC(50) of 43+/-12 microM. Magnesium gave a marked activation in the range between 1 and 20 mM with maximum effect at 10 mM. The other divalent cations, Mn(2+) and Co(2+), were unable to substitute Mg(2+), but caused some activation at 1 mM. EDTA and EGTA stimulated cGMP transport concentration-dependently with 50% and 100% above control at 100 microM, respectively. The present study shows that the cGMP pump has properties compatible with an organic anion transport ATPase, without affinity for the MRP substrate LTC(4). However, the blockade of the cGMP transporter by glutathione S-conjugates suggests it is one of several GS-X pumps.  (+info)

An in vivo approach showing the chemotactic activity of leukotriene B(4) in acute renal ischemic-reperfusion injury. (14/415)

Neutrophil migration protects the body against foreign invasion. Sequestration and activation of neutrophils, however, require stringent regulation because they may also cause tissue damage by the release of lysosomal enzymes and reactive oxygen species. The activity of various chemoattractants [e.g., leukotriene B(4) (LTB(4)), interleukin-8, and complements] has been documented by in vitro assays, whereas in vivo data have been limited mostly to histology. To examine in an in vivo model the chemotactic activity and subsequent tissue infiltration and the role of a specific chemoattractant, LTB(4), we used a rat renal ischemia-reperfusion injury model. Fluorescence-labeled Chinese hamster ovary (CHO) cells stably expressing the LTB(4) receptor (CHO-BLT) were able to accumulate along with neutrophils in the postischemic kidney, in contrast to vector control CHO cells. Furthermore, LTB(4) antagonists that protect against the decrease in renal function and diminish the tissue myeloperoxidase activity also led to the marked decrease in the number of CHO-BLT cells and neutrophils. Thus, LTB(4) alone appears sufficient to cause cells to migrate into postischemic tissues, and its dominant role in reperfusion injury has been demonstrated. The utilization of transfectants to pinpoint the role of LTB(4) in these in vivo experiments suggests their potential use with other ligands and/or in other pathological conditions.  (+info)

LTA(4)-derived 5-oxo-eicosatetraenoic acid: pH-dependent formation and interaction with the LTB(4) receptor of human polymorphonuclear leukocytes. (15/415)

5-oxo-(7E,9E,11Z,14Z)-eicosatetraenoic acid (5-oxo-ETE) has been identified as a non-enzymatic hydrolysis product of leukotriene A(4) (LTA(4)) in addition to 5,12-dihydroxy-(6E,8E,10E, 14Z)-eicosatetraenoic acids (5,12-diHETEs) and 5,6-dihydroxy-(7E,9E, 11Z,14Z)-eicosatetraenoic acids (5,6-diHETEs). The amount of 5-oxo-ETE detected in the mixture of the hydrolysis products of LTA(4) was found to be pH-dependent. After incubation of LTA(4) in aqueous medium, the ratio of 5-oxo-ETE to 5,12-diHETE was 1:6 at pH 7.5, and 1:1 at pH 9.5. 5-Oxo-ETE was isolated from the alkaline hydrolysis products of LTA(4) in order to evaluate its effects on human polymorphonuclear (PMN) leukocytes. 5-Oxo-ETE induced a rapid and dose-dependent mobilization of calcium in PMN leukocytes with an EC(50) of 250 nM, as compared to values of 3.5 nM for leukotriene B(4) (LTB(4)500 nM for 5(S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoic acid (5-HETE). Pretreatment of the cells with LTB(4) totally abolished the calcium response induced by 5-oxo-ETE. In contrast, the preincubation with 5-oxo-ETE did not affect the calcium mobilization induced by LTB(4). The calcium response induced by 5-oxo-ETE was totally inhibited by the specific LTB(4) receptor antagonist LY223982. These data demonstrate that 5-oxo-ETE can induce calcium mobilization in PMN leukocyte via the LTB(4) receptor in contrast to the closely related analog 5-oxo-(6E,8Z,11Z, 14Z)-eicosatetraenoic acid which is known to activate human neutrophils by a mechanism independent of the receptor for LTB(4).  (+info)

Role of antileukotriene agents in asthma therapy. (16/415)

Leukotrienes are proinflammatory mediators with special significance in asthma. Released by numerous cell types, particularly after exposure to allergens, leukotrienes cause a potent contraction of bronchial smooth muscle, resulting in reduced airway caliber. Further, they cause plasma to leak from the vessels, resulting in edema, and enhance the secretion of mucus--both events that increase airway obstruction. Thus, leukotrienes have been a target of basic research in asthma. To date, a number of antileukotriene agents have been developed, and three are currently being used in clinical practice in the United States: zafirlukast and montelukast act by antagonizing the leukotriene receptor, and zileuton inhibits leukotriene synthesis. Studies have shown that these agents improve asthma symptoms, pulmonary function, and patient quality of life. Antileukotriene agents have generally been associated with a low incidence of side effects and good tolerability. Currently recommended for mild-to-moderate, persistent asthma, these agents have enabled patients to reduce their use of corticosteroids.  (+info)