leukotriene-b4 and Rhinitis--Allergic--Perennial

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Airway Resistance; Calcium Channel Blockers; Chemotactic Factors, Eosinophil; Cholinergic Antagonists; Cromolyn Sodium; Glucocorticoids; Histamine; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Nasal Mucosa; Nasal Provocation Tests; Nose; Prostaglandins; Rhinitis, Allergic, Perennial; Thromboxanes

Prostaglandins and leukotrienes are implicated in conditions of both the upper and lower airways. In the former they are deranged in nasal polyposis, intrinsic rhinitis and allergic rhinitis while in the latter they are involved in the pathogenesis of asthma. The aim of the present study was to measure mucosal eicosanoid levels in the three types of rhinitis and compare with controls. In addition, the effect of topical steroids on eicosanoid levels in rhinitis was examined. The levels of prostaglandins E(2) (PGE(2)) and D(2) (PGD(2)) and of leukotrienes E(4) (LTE(4)) and B(4) (LTB(4)) were measured in nasal biopsies from the inferior turbinates of patients suffering from perennial rhinitis and a control group. Rhinitis patients were classified into three categories: perennial allergic rhinitis (PAR), non-allergic rhinitis with eosinophilia (NARES) and noneosinophilic non-allergic rhinitis (NENAR) on the basis of symptoms, secretion eosinophilia, nasal resistance and allergy testing. Patients with rhinitis were randomized into two groups. One received fluticasone propionate nasal spray (FPANS) and the other a placebo (PNS) over a period of six weeks prior to the biopsies. One hundred and one patients with PAR, NARES or NENAR were recruited sequentially and the control group consisted of 21 patients with no evidence of rhinitis but with nasal obstruction due to septal deviation. Untreated rhinitics had significantly lower levels of PGE(2), PGD(2) and LTE(4) than non-rhinitic controls. Six-weeks' treatment with FPANS significantly increased the levels of those eicosanoids in patients with PAR and NARES but they were still significantly below normal. Levels of LTB(4) in all three rhinitis groups were not significantly different from controls and treatment with topical steroids had no effect. Their findings are contrary to current thinking that increased levels of eicosanoids, in particular cysteinyl-leukotrienes, play an important role in the pathogenesis of chronic, non-infective upper airway inflammation.

Topics: Airway Resistance; Androstadienes; Anti-Inflammatory Agents; Chronic Disease; Dinoprostone; Double-Blind Method; Eosinophils; Fluticasone; Humans; Leukocyte Count; Leukotriene B4; Leukotriene E4; Leukotrienes; Nasal Mucosa; Nasal Polyps; Prostaglandin D2; Prostaglandins; Rhinitis; Rhinitis, Allergic, Perennial

The reduction of symptoms due to treatment with corticosteroids varies among patients with perennial rhinitis. Most patients will respond but a few patients respond less to these drugs.. To investigate the association in reduction of symptoms due to glucocorticoids and glucocorticoid receptor characteristics in patients with perennial allergic rhinitis, in vitro glucocorticoid receptor binding studies were performed with peripheral blood mononuclear cells using dexamethasone and in vitro production of mediators were measured.. During a double-blind placebo-controlled crossover study, 200 micrograms fluticasone propionate aqueous nasal spray (in the active treatment period) and placebo (in the placebo treatment period) were administered twice daily for 2 weeks to 22 patients allergic to house dust mite. At the end of both treatment periods symptoms were scored after allergen provocation (100, 1000, 10000 BU/mL) and during the 9.5 hours after this challenge. Receptor binding studies with dexamethasone were performed with peripheral blood mononuclear cells. Leukotriene B4 produced by monocytes in vitro and soluble interleukin-2 receptor released by lymphocytes in vitro and cortisol levels in plasma were determined.. No significant partial correlations of the number of the peripheral blood mononuclear cell glucocorticoid receptors (6821 +/- 5669 binding sites per cell) and the affinity (Kd: 16.5 +/- 13.51 nmol/L) for the glucocorticoid receptors with the symptom score (placebo: 4.3 +/- 2.45 pts; fluticasone: 2.4 +/- 1.55 pts) after active treatment were found. Also no significant partial correlations of the levels of leukotriene B4 (45.6 +/- 105.3 ng/10(6) cells) produced by monocytes in vitro, soluble interleukin-2 receptor (734 +/- 237 ng/10(6) cells) released by lymphocytes in vitro and cortisol levels (571 +/- 236 ng/mL) in plasma with the symptom score after active treatment were found.. The reduction of symptoms due to topical fluticasone propionate in patients with rhinitis and allergy to house dust mite is not correlated with the characteristics of the glucocorticoid receptor.

Topics: Administration, Intranasal; Adult; Androstadienes; Anti-Inflammatory Agents; Cross-Over Studies; Double-Blind Method; Female; Fluticasone; Humans; Hydrocortisone; Leukocytes, Mononuclear; Leukotriene B4; Male; Middle Aged; Receptors, Glucocorticoid; Receptors, Interleukin-2; Rhinitis, Allergic, Perennial; Solubility

The clinical importance of leukotrienes in human allergy has not been defined, in part because there have been no selective 5-lipoxygenase inhibitors that have been effective and safe for use in humans. To address the hypothesis that stimulated leukotriene synthesis causes symptoms of immediate-hypersensitivity reactions in vivo, I investigated the effects of a new 5-lipoxygenase inhibitor, A-64077, on provoked allergic nasal symptoms and mediator release in a double-blind, randomized, placebo-controlled study. Eight subjects with allergic rhinitis underwent nasal challenge on two occasions after an oral dose of 800 mg of A-64077 or an identical-appearing placebo.. Allergen-induced nasal congestion was significantly attenuated (P less than 0.02) by A-64077; peak levels of leukotriene B4 (median, 684 pg per milliliter) and 5-hydroxyeicosatetraenoic acid (median, 704 pg per milliliter) in nasal-rinse fluids were markedly reduced (to 67 and 185 pg per milliliter, respectively; P less than 0.01), whereas levels of prostaglandin D2 were not. Histamine release and sneezing were not reduced significantly by A-64077, but there was a significant correlation (P less than 0.01) between the changes in these variables within subjects. The mean (+/- SEM) stimulated synthesis of leukotriene B4 in whole blood ex vivo was markedly reduced by A-64077 (from 153 +/- 19 to 20 +/- 9 ng per milliliter, P less than 0.01), and the specificity of A-64077 for 5-lipoxygenase inhibition was verified by its lack of effect on the synthesis of serum thromboxane B2 or 12-hydroxyeicosatetraenoic acid.. These results provide direct evidence of an important role for the 5-lipoxygenase products of arachidonic acid in allergic rhinitis and support the notion that further experiments in this area may lead to new therapeutic approaches to allergic disorders.

Topics: Double-Blind Method; Female; Histamine Release; Humans; Hydroxyeicosatetraenoic Acids; Hydroxyurea; Leukotriene B4; Leukotrienes; Lipoxygenase Inhibitors; Male; Nasal Obstruction; Nasal Provocation Tests; Prostaglandin D2; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sneezing

Leukotriene B4 (LTB4), a potent chemokinetic mediator for neutrophils, is enhanced by interleukin-8 (IL-8) and may play a key role in the inflammatory response of asthma.. The aim of the present study was to investigate whether zileuton, a 5-lipoxygenase antagonist known to inhibit LTB4 production and recruitment of eosinophils/neutrophils in bronchoalveolar fluid, could affect the production of LTB4 and IL-8 by allergen-stimulated peripheral blood mononuclear cells in vitro from patients with asthma and/or allergic rhinitis.. Peripheral blood mononuclear cells were isolated using Ficoll-Hypaque density gradient from 14 subjects (2 with asthma, 11 with asthma and allergic rhinitis, and 1 with allergic rhinitis) and were stimulated by selected allergens (grass, tree, mite, and mold) in the absence or presence of 1 and 10 microM of zileuton. Supernatants were collected and assayed for LTB4 and IL-8 levels using RIA and ELISA, respectively.. Levels of LTB4 were significantly elevated in peripheral blood mononuclear cells stimulated with mold, grass, and tree compared with the unstimulated control group (P<.05). Levels of IL-8 were significantly elevated in all allergen-stimulated peripheral blood mononuclear cells, except mold, compared with the unstimulated control group (P<.05). Zileuton significantly reduced production of LTB4 by mold and tree-stimulated peripheral blood mononuclear cells. By contrast, no effect of zileuton on IL-8 production was observed in allergen-stimulated peripheral blood mononuclear cells.. The zileuton-induced attenuation of LTB4 production by allergen-stimulated peripheral blood mononuclear cells from patients with asthma and/or allergic rhinitis occurs independently from the allergen-stimulated IL-8 production.

Topics: Adult; Aged; Allergens; Asthma; Female; Humans; Hydroxyurea; Interleukin-8; Leukocytes, Mononuclear; Leukotriene B4; Lipoxygenase Inhibitors; Male; Middle Aged; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

Mucosal inflammatory processes in late phase of allergic diseases involve cytokine production, cell adhesion molecule overexpression and release of inflammatory mediators with chemotactic activity, such as leukotriene B4 (LTB4). We had previously observed increased production of LTB4 by neutrophils in patients with allergic rhinitis and discussed the role of granulocyte macrophage-colony stimulating factor (GM-CSF) priming. Some antihistaminic compounds were shown to diminish the production of leukotrienes by neutrophils.. In a first step, we evaluated in ex vivo and in vitro studies, the effects of cetirizine on LTB4 production by blood neutrophils from allergic and healthy subjects. In a second step, we studied the in vitro effect of cetirizine on LTB4 production by neutrophils from healthy subjects during GM-CSF priming of these cells.. Neutrophils from both populations were purified from venous blood and LTB4 production was measured using high performance liquid cromatography (HPLC) method.. In ex vivo studies, cetirizine treatment induced a decreased LTB4 production by neutrophils in allergic rhinitis. This effect of decreased LTB4 production was reproduced in vitro with 10(-8)-10(-6)M cetirizine. Nevertheless, this anti-H1 compound had no effect on neutrophil priming with GM-CSF.. As LTB4 is an important chemotactic factor, Cetirizine could act on inflammatory cell recruitment by inhibiting LTB4 production by neutrophils.

Topics: Adult; Anti-Allergic Agents; Asthma; Cetirizine; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine H1 Antagonists; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Rhinitis, Allergic, Perennial

To determine whether nasal allergic symptoms can cause bronchial hyperresponsiveness to methacholine, 30 subjects with allergic rhinitis (22 with allergic rhinitis and 8 with allergic asthmatic rhinitis) were studied. All subjects were skin test positive to Dermatophagoides pteronyssinus (DP) and underwent nasal allergic provocation with DP. After provocation, there was a severe nasal allergic reaction in the challenged nostril with a significant increase in nasal resistance both immediately and long (7 h) after DP exposure. There were no significant changes in the forced expiratory volume in 1 s and the forced expiratory flow rate between 25 and 75% of the forced vital capacity and in both allergic rhinitis and allergic asthmatic rhinitis patients. There was also no change in bronchial hyperresponsiveness to methacholine. The eosinophil counts, leukotriene B4, leukotriene C4 and platelet-activating factor levels in nasal discharges also showed no differences in both groups of patients. Our studies suggest that nasal provocation with limited allergen is a safe diagnostic technique. However, the relationship between nasal resistance and airway hyperreactivity is not obvious in this study. The similar concentrations of nasal inflammatory mediators in both allergic rhinitis and allergic asthmatic rhinitis indicate that bronchial hyperreactivity is not solely due to nasal drainage of inflammatory mediators.

Topics: Adolescent; Adult; Allergens; Antigens, Dermatophagoides; Bronchial Hyperreactivity; Eosinophils; Female; Glycoproteins; Humans; Leukocyte Count; Leukotriene B4; Leukotriene C4; Male; Methacholine Chloride; Nasal Mucosa; Nasal Provocation Tests; Platelet Activating Factor; Rhinitis, Allergic, Perennial

The purpose of this study is to examine the "in vivo" release of 15-HETE and other arachidonic acid metabolites in nasal secretions following a challenge with "Dermatophagoides Pteronyssinus" in patients with allergic rhinitis and non-allergic controls. In addition, we examine the effects of a membrane stabilizer, such as sodium cromoglycate, on these metabolites. Thirteen allergic subjects and seven healthy controls are studied. 15-HETE, peptide leukotrienes, LTB4, PGD2, PGE2 and PGF2 alpha levels are evaluated before and after nasal challenge in sodium cromoglycate treated and untreated subjects. This study provides "in vivo" evidence that the pathophysiological responses to nasal antigen challenge could be related to the release of 15-HETE as well as other arachidonic acid metabolites, mainly arising from the lipoxygenase pathway.

Topics: Adolescent; Adult; Analysis of Variance; Arachidonic Acid; Cromolyn Sodium; Dinoprost; Dinoprostone; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Male; Middle Aged; Nasal Mucosa; Nasal Provocation Tests; Prostaglandin D2; Rhinitis, Allergic, Perennial

Leukotrienes are a recently discovered group of arachidonic acid-derived lipid mediators. Using radioimmunoassay and high pressure liquid chromatography (HPLC), we have identified the SRS-A sulphidopeptide leukotrienes (LTC4, LTD4 and LTE4) in nasal washings from patients with allergic rhinitis who underwent nasal challenge with specific allergen. Smaller, but significant, amounts of LTB4 were also detected. The concentrations of nasal leukotrienes were directly related to the dose of allergen, and were recovered in washings in a time-dependent fashion after challenge. When the patients were subjected to methacholine nasal challenge on a control day, we found only negligible amounts of either the sulphidopeptide leukotrienes or LTB4. These findings support the view that LTC4, LTD4 and LTE4 might contribute to the pathogenesis of allergic rhinitis as a result of their recognized effects on mucous hypersecretion and vasopermeability, and that the potent chemoattractant LTB4 might be involved in the subsequent infiltration of inflammatory cells.

Topics: Adult; Animals; Antigens; Humans; Leukotriene B4; Methacholine Compounds; Middle Aged; Mites; Nasal Provocation Tests; Pollen; Radioimmunoassay; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; SRS-A