prostaglandin-d2 and Rhinitis--Allergic--Seasonal

Topics: Histamine; Humans; Kinins; Leukotrienes; Nasal Obstruction; Platelet Activating Factor; Prostaglandin D2; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Substance P

Various mediator systems have been stressed as important in the generation of the signs and symptoms of allergic disease such as hay fever. Nevertheless, in the upper airways, histamine is still the only mediator which behaves consistently in terms of release at appropriate challenge, produces all the major symptoms of rhinitis at a local challenge, and the specific antagonist influences the signs and symptoms of rhinitis in the challenge situation as well as during natural allergen exposure. Although the majority of hay fever symptoms are influenced by H1-receptors, there are exceptions. An important one is the symptom of nasal blockage, which is due to tissue oedema and a decrease in the tone of the capacitance vessels. Another point to be stressed is that histamine alone does not induce any protracted mucosal inflammatory response with associated symptoms, influx of eosinophils and increase in responsiveness that is associated with the exposure to allergen. Nevertheless, from a clinical point of view, antihistamines are still valuable pharmacological agents for the clinical management of hay fever symptoms.

Topics: Histamine H1 Antagonists; Histamine Release; Humans; Nasal Provocation Tests; Prostaglandin D2; Rhinitis, Allergic, Seasonal

Antigen and cold dry air were used to challenge the upper and lower airways, skin, and conjunctiva. In each of these four systems an immediate and late-phase reaction to antigen is well characterized. Although the pattern of mediator release is different in these four areas, the degree of infiltration of basophils and eosinophils in the late-phase reaction appears to be constant. Of a number of drugs that can influence these mediators and cell responses, the steroids represent a typical mode of action. Steroids block the late-phase response and ablate the eosinophil and basophil infiltration. Although the effects of antihistamines appear to be similar, they do not appear to be caused by H1 antagonism; the mechanism of their action is unknown. This discussion will focus on these non-H1 antagonist effects of antihistamines in four challenge models, particularly the upper airways and skin.

Topics: Benzhydryl Compounds; Cetirizine; Cyproheptadine; Dermatitis, Atopic; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Hydroxyzine; Prostaglandin D2; Rhinitis, Allergic, Seasonal; SRS-A; Terfenadine

Botanical products are frequently used for treatment of nasal allergy. Three of these substances, Cinnamomum zeylanicum, Malpighia glabra, and Bidens pilosa, have been shown to have a number of anti-allergic properties in-vitro. The current study was conducted to determine the effects of these combined ingredients upon the nasal response to allergen challenge in patients with seasonal allergic rhinitis.. Twenty subjects were randomized to receive the combination botanical product, (CBP) 2 tablets three times a day, loratadine, 10 mg once a day in the morning, or placebo, using a randomized, double-blinded crossover design. Following 2 days of each treatment and during the third day of treatment, subjects underwent a nasal allergen challenge (NAC), in which nasal symptoms were assessed after each challenge dose and every 2 hours for 8 hours. Nasal lavage fluid was assessed for tryptase, prostaglandin D2, and leukotriene E4 concentrations and inflammatory cells.. Loratadine significantly reduced the total nasal symptom score during the NAC compared with placebo (P = 0.04) while the CBP did not. During the 8 hour period following NAC, loratadine and the CBP both reduced NSS compared with placebo (P = 0.034 and P = 0.029, respectively). Analysis of nasal lavage fluid demonstrated that the CBP prevented the increase in prostaglandin D2 release following NAC, while neither loratadine nor placebo had this effect. None of the treatments significantly affected tryptase or leukotriene E4 release or inflammatory cell infiltration.. The CBP significantly reduced NSS during the 8 hours following NAC and marginally inhibited the release of prostaglandin D2 into nasal lavage fluid, suggesting potential clinical utility in patients with allergic rhinitis.

Topics: Adolescent; Adult; Aged; Anti-Allergic Agents; Bidens; Cinnamomum zeylanicum; Cross-Over Studies; Double-Blind Method; Drugs, Chinese Herbal; Female; Humans; Loratadine; Male; Malpighiaceae; Middle Aged; Nasal Mucosa; Nasal Provocation Tests; Phytotherapy; Pilot Projects; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Treatment Outcome

Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D(2) is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD(2) reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD(2) (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD(2) can be a useful tool for evaluating DP-receptor antagonists.. The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD(2) induced nasal congestion in healthy volunteers.. To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD(2) were performed to determine the PD(75), which is the intranasal dose of PGD(2) that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry.. Following treatment with MK-0524, the PD(75) (mean+/-SD) was significantly shifted from 15.8 +/- 18.3 mug/nostril during the placebo period to more than 512 mug/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen.. Whether this >45 fold increase in PD(75) will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.

Topics: Administration, Oral; Adult; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indoles; Male; Nasal Obstruction; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic, Seasonal; Rhinomanometry

Histamine antagonists together with topical steroids are the treatment of choice in allergic rhinitis. Many of these histamine antagonists exhibit effects in addition to blockade of the histamine receptor. In this study we have investigated the effects of ebastine and carebastine on the release of eicosanoids and cytokines from human dispersed polyp cells and the effect of these compounds on the release of inflammatory mediators into nasal lavage fluid after allergen challenge. Ebastine was shown to block the release of anti-IgE-induced prostaglandin D2 (PGD2) and leukotriene C4/D4 from human nasal polyp cells (IC30 values of 2.57 and 9.6 mumol/L, respectively) and to inhibit the release of cytokines. Carebastine inhibited the release of PGD2 (IC30 8.14 mumol/L) but had little effect on cytokine release. When patients underwent nasal provocation tests with allergen, ebastine significantly increased the mean number of pollen grains required to induce an allergic response. In addition, the drug inhibited the release of granulocyte-macrophage colony-stimulating factor but had no effect on any other mediators measured.

Topics: Adolescent; Adult; Allergens; Butyrophenones; Cross-Over Studies; Double-Blind Method; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Histamine H1 Antagonists; Humans; Leukotriene C4; Male; Middle Aged; Nasal Polyps; Piperidines; Pollen; Prostaglandin D2; Rhinitis, Allergic, Seasonal

The aim of the study was to investigate the effect of short-term treatment with fluticasone propionate on the response to nasal allergen challenge in patients with allergic rhinitis. Responses to nasal allergen challenge were assessed subjectively by recording symptom scores on visual analogue scales, and objectively by measuring histamine, PGD2 and LTC4 in nasal lavage and by measuring nasal inspiratory peak flow following challenge. Nasal allergen challenge resulted in an increase in all symptom scores (P < 0.05); an increase in histamine and PGD2 (P < 0.05), and a decrease in nasal inspiratory peak flow at 1 h, 5 h and 7 h following challenge (P < 0.05). The allergen-induced changes in symptom scores, mediator levels and nasal inspiratory peak flow were attenuated by treatment with fluticasone propionate (P < 0.05 for all parameters measured). Post-challenge nasal obstruction was decreased by 45%; sneezing, itching and rhinorrhoea by 73, 78 and 80% respectively in the group as a whole comparing scores whilst on fluticasone propionate with those on no therapy. Fluticasone propionate, 200 micrograms twice daily for 2 weeks is effective in reducing significantly the early and late response to nasal allergen challenge.

Topics: Administration, Intranasal; Adult; Allergens; Androstadienes; Anti-Inflammatory Agents; Female; Fluticasone; Glucocorticoids; Histamine; Humans; Inspiratory Capacity; Leukotriene C4; Male; Middle Aged; Nasal Lavage Fluid; Poaceae; Pollen; Prostaglandin D2; Radioimmunoassay; Rhinitis, Allergic, Seasonal

Allergic rhinitis is characterized by a profuse rhinorrhea in addition to paroxysms of sneezing, nasal congestion, and pruritus. To define better the sources of nasal secretion produced during rhinitis, nasal allergen challenges were performed on nine atopic subjects with seasonal rhinitis. A single dose of allergen was sprayed into one side of the nose, and nasal lavages were collected bilaterally for 7 hours. Nasal lavages were assayed for protein (total protein, albumin, lactoferrin, and lysozyme) and mediator (histamine and prostaglandin D2) content. Protein concentrations increased and remained elevated above baseline levels in both ipsilateral and contralateral secretions for up to 3 hours after allergen challenge. The proportion of albumin relative to total protein (the albumin percent) increased on the ipsilateral side, whereas the relative proportions of lactoferrin and lysozyme (the lactoferrin percent and lysozyme percent) increased on the contralateral side. Prostaglandin D2, but not histamine, increased selectively on the ipsilateral side. These data suggest that the ipsilateral protein secretory response is due to allergen-induced mast cell mediator release causing increased vascular permeability, whereas the contralateral protein secretory response is primarily a reflex-induced glandular secretion.

Topics: Adult; Albumins; Allergens; Female; Histamine; Histamine Release; Humans; Lactoferrin; Male; Muramidase; Nasal Cavity; Nasal Mucosa; Nasal Provocation Tests; Prostaglandin D2; Proteins; Rhinitis, Allergic, Seasonal; Therapeutic Irrigation; Time Factors

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

Antigen and cold dry air were used to challenge the upper and lower airways, skin, and conjunctiva. In each of these four systems an immediate and late-phase reaction to antigen is well characterized. Although the pattern of mediator release is different in these four areas, the degree of infiltration of basophils and eosinophils in the late-phase reaction appears to be constant. Of a number of drugs that can influence these mediators and cell responses, the steroids represent a typical mode of action. Steroids block the late-phase response and ablate the eosinophil and basophil infiltration. Although the effects of antihistamines appear to be similar, they do not appear to be caused by H1 antagonism; the mechanism of their action is unknown. This discussion will focus on these non-H1 antagonist effects of antihistamines in four challenge models, particularly the upper airways and skin.

Topics: Benzhydryl Compounds; Cetirizine; Cyproheptadine; Dermatitis, Atopic; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Hydroxyzine; Prostaglandin D2; Rhinitis, Allergic, Seasonal; SRS-A; Terfenadine

To investigate the kinetics and pattern of allergenically induced mediator release in the human skin, we have studied 24 ragweed- and grass-allergic patients with a blister-chamber technique. Chambers sealed to the skin around a denuded area, formed by unroofing a blister, were challenged with 0.5 ml of either diluent or 10 or 100 times the concentration of allergen required for 4+ early intradermal reaction. Chamber fluids were removed hourly 1 to 8 hours after antigen challenge and examined for the presence of histamine, leukotriene C4 (LTC4), and prostaglandin D2 to compare inflammatory mediator levels with the clinical early response and late-phase response (LPR), as assessed by erythema around the chamber. An initial erythema developed rapidly and began to subside after 1 hour in all patients, but a late-phase local erythema and subcutaneous swelling around the chamber (i.e., greater than 2.5 cm, the outside diameter of the chamber) developed in 13/15 challenges only when the higher concentration of antigen was used. At both allergen concentrations, histamine levels peaked sharply at the first hour (20.6 +/- 2.3 ng/ml) and progressively declined during the next 4 hours by 75%, but remained above control levels for at least 7 hours. Despite high control values, LTC4 levels were significantly elevated (p less than 0.01) 4 to 6 hours after challenge. In visible reactions, maximal LPR around the chamber correlated with LTC4 levels obtained 6 and 7 hours after challenge (p less than 0.05). Prostaglandin D2 rose gradually in antigen-challenged chambers to a peak at 5 to 6 hours. Thus, early rises in histamine were temporally related to the immediate erythema, whereas the arachidonic acid metabolites from both cyclooxygenase and lipoxygenase pathways that appeared in the skin after allergen challenge followed kinetics that corresponded to the time course of cutaneous LPR.

Topics: Adolescent; Adult; Antigens; Erythema; Female; Histamine Release; Humans; Kinetics; Male; Middle Aged; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Skin; Skin Tests; Skin Window Technique; SRS-A; Time Factors

A double blind, placebo-controlled, cross-over study was performed to determine the effect of cetirizine, an H1 antihistamine, on the immediate nasal allergic response. Ten persons underwent nasal challenge with antigen after premedication with 20 mg of cetirizine or placebo QD for 2 days. The response was monitored by counting the number of sneezes and by measuring the levels of histamine, prostaglandin D2, leukotriene C4, albumin, and TAME-esterase activity in recovered nasal lavages. The results showed a significant reduction in sneezing and in the amounts of recovered albumin, TAME-esterase activity, and leukotriene C4 but no reduction in the amounts of recovered histamine and prostaglandin D2. These results suggest that cetirizine does not inhibit mast cell activation but inhibits the consequences of the released histamine on H1 receptors: sneezing and increased vascular permeability. The results further suggest that mast cell release of histamine is the direct result of antigen stimulation, as opposed to reflex activation, and that other cells in addition to mast cells generate leukotrienes during the early allergic response.

Topics: Albumins; Antigens; Cetirizine; Clinical Trials as Topic; Double-Blind Method; Histamine; Histamine H1 Antagonists; Humans; Hydroxyzine; Nasal Mucosa; Peptide Hydrolases; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Sneezing

Most oral drugs used for the treatment of allergic rhinitis are classified as H1-receptor antagonists, and although they represent major sales throughout the world, their mechanism of action is still poorly known. In an attempt to understand better the in vivo therapeutic effects of these drugs, a double-blind, crossover study was carried out. The study compared the effects of terfenadine and loratadine, nonsedative H1-receptor antagonists, on the immediate allergic response of the upper airways to challenge with orchard-grass pollens in 14 highly allergic subjects. Increasing numbers of pollen grains were insufflated into the nostrils, and the response of the subjects was assessed by examining symptoms and measuring the release of histamine and prostaglandin D2 in nasal secretions. Each drug was administered for a week before challenge. This study demonstrated the clinical efficacy of both drugs by comparison to that of a control day, since symptoms were observed for a significantly (p = 0.014) greater number of pollen grains. Only one patient had a significant release of histamine when they were treated with loratadine versus 10 during control day (p less than 0.0023) and six when they were treated with terfenadine (p less than 0.01). Prostaglandin D2 release occurred with a higher allergen dose when patients were treated with both drugs. This study indicates that some H1 antagonists also possess antiallergic activities.

Topics: Adult; Benzhydryl Compounds; Cyproheptadine; Double-Blind Method; Histamine H1 Antagonists; Histamine Release; Humans; Loratadine; Nasal Provocation Tests; Pollen; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Terfenadine

Although it has been suggested that prostaglandin (PG) D(2) is involved in the pathogenesis of allergic rhinitis, whether the inhibition of hematopoietic PGD(2) synthase (H-PGDS) shows beneficial effects on allergic rhinitis has been unclear. We evaluated the effects of a selective H-PGDS inhibitor, TFC-007, on nasal symptoms on Japanese cedar pollen-induced allergic rhinitis of guinea pigs. Sensitized animals were challenged with the pollen once a week. TFC-007 (30mg/kg, p.o.) given once before a challenge almost completely suppressed PGD(2) production in the nasal tissue early and late after the challenge. Although pre-treatment did not affect the incidences of sneezing and early phase nasal blockage, late phase nasal blockage was partially but significantly attenuated; however, nasal eosinophilia was not suppressed. In contrast, when TFC-007 was given once 1.5h after the challenge, the late phase response was not affected. Collectively, PGD(2) produced by H-PGDS early after an antigen challenge can participate in the induction of late phase nasal blockage, although the mechanism may be independent of eosinophil infilatration. The strategy for H-PGDS inhibition may be beneficial for allergic rhinitis therapy.

Topics: Allergens; Animals; Cryptomeria; Enzyme Assays; Eosinophilia; Eosinophils; Guinea Pigs; Humans; Intramolecular Oxidoreductases; Lipocalins; Morpholines; Nasal Lavage Fluid; Nasal Obstruction; Pollen; Prostaglandin D2; Pyrimidines; Rhinitis, Allergic, Seasonal; Sneezing

PGD(2) is the major prostanoid produced during the acute phase of allergic reactions. Two PGD(2) receptors have been isolated, DP and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), but whether they participate in the pathophysiology of allergic diseases remains unclear. We investigated the role of CRTH2 in the initiation of allergic rhinitis in mice. First, we developed a novel murine model of pollinosis, a type of seasonal allergic rhinitis. Additionally, pathophysiological differences in the pollinosis were compared between wild-type and CRTH2 gene-deficient mice. An effect of treatment with ramatroban, a CRTH2/T-prostanoid receptor dual antagonist, was also determined. Repeated intranasal sensitization with Cry j 1, the major allergen of Cryptomeria japonica pollen, in the absence of adjuvants significantly exacerbated nasal hyperresponsive symptoms, Cry j 1-specific IgE and IgG1 production, nasal eosinophilia, and Cry j 1-induced in vitro production of IL-4 and IL-5 by submandibular lymph node cells. Additionally, CRTH2 mRNA in nasal mucosa was significantly elevated in Cry j 1-sensitized mice. Following repeated intranasal sensitization with Cry j 1, CRTH2 gene-deficient mice had significantly weaker Cry j 1-specific IgE/IgG1 production, nasal eosinophilia, and IL-4 production by submandibular lymph node cells than did wild-type mice. Similar results were found in mice treated with ramatroban. These results suggest that the PGD(2)-CRTH2 interaction is elevated following sensitization and plays a proinflammatory role in the pathophysiology of allergic rhinitis, especially pollinosis in mice.

Topics: Allergens; Animals; Antigens, Plant; Carbazoles; Cryptomeria; Cytokines; Disease Models, Animal; Eosinophils; Immunoglobulins; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Nasal Mucosa; Nasal Septum; Plant Proteins; Pollen; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic, Seasonal; Sulfonamides; Th2 Cells

Allergen challenge in some patients with respiratory allergy is followed by an early and a late reaction.. To evaluate the duration of mediator release and inflammatory cell recruitment during the late antigen-induced nasal response.. Eight patients with seasonal allergic rhinitis due to grass pollen underwent local challenge with the relevant allergen, a non-relevant allergen (Parietaria judaica), and nebulized saline solution. Nasal lavages were performed at baseline and 6, 24, 48, 72 h after challenge. Eosinophil cationic protein (ECP), leukotriene C4 (LTC4), leukotriene B4 (LTB4) myeloperoxidase (MPO) and prostaglandin D2 (PGD2) levels were radioimmunoassayed and histamine concentration was measured by an automated fluorometric method.. Nasal challenge with the relevant antigen induced a response 6 h after stimulation, which subsided within 24 h. Eosinophilia, observed in the nasal lavages collected from 6 to 24 h after this challenge, was accompanied by ECP release. Neutrophilia were found in the nasal lavages collected from 6 to 24 h after challenge. The increase in neutrophil number correlated with MPO levels and LTB4 concentrations, but not with the intensity of nasal obstruction. Antigen challenge also induced significant recruitment of mononuclear cells 48 h after provocation. The challenge significantly raised histamine, but not PGD2, levels in the nasal lavages collected 6 h after provocation. A trend towards an increase in LTC4 levels in the nasal lavages collected 6 h after specific antigen challenge was also found. Nasal challenge with a non-relevant allergen or with saline solution did not cause either inflammatory cell recruitment or mediator release.. Nasal challenge with the relevant antigen can induce a late response characterized by local accumulation of eosinophils, neutrophils and mononuclear cells persisting for 48 h and accompanied by release of ECP, MPO, LTB4 and histamine. These results indicate that a single antigen challenge in patients with allergic rhinitis causes prolonged inflammatory alterations which may contribute to the development of airway hyperreactivity.

Topics: Adolescent; Adult; Antigens; Blood Proteins; Chemotaxis, Leukocyte; Eosinophil Granule Proteins; Eosinophils; Female; Histamine; Humans; Leukocytes, Mononuclear; Leukotriene B4; Leukotriene C4; Male; Nasal Lavage Fluid; Nasal Provocation Tests; Neutrophils; Peroxidase; Pollen; Prostaglandin D2; Radioimmunoassay; Rhinitis, Allergic, Seasonal; Ribonucleases

By using a microsuction technique, a quantitative determination of chemical mediators in nasal secretions was performed in 18 hay-fever patients and in a control group of 10 healthy volunteers. The authors then compared these quantitative data for mediators with objective nasal findings counting the number of sneezes, passive anterior rhinomanometry (PAR) and nasal inspiratory peak flow. A sampling protocol was designed with a follow-up of 3 days after nasal allergen challenge (NAC) in order to investigate both early and late allergic reactions. Median baseline concentrations of five major mediators were obtained: histamine, 19 ng/g; leukotriene C4 (LTC4), 5.7 ng/g. tryptase, 0; prostaglandin D2 (PGD2), 477 pg/g; eosinophil cationic protein (ECP), 105 ng/g. Significant increases in histamine (214 ng/g), LTC4 (20 ng/g) and tryptase (28 microU/g) were found, but a significant decrease occurred in ECP (47 ng/g) and PGD (226 pg/g) immediately after NAC in the patients studied. Most ECP concentrations (94%) increased slowly 1 h after NAC and reached a significantly higher level 24 h later. In evaluating nasal symptoms, sneezes were present in a high percentage of cases (76%) during the early phase but were uncommon during the late phase (29%). Total nasal obstruction occurred in 94% during the early phase. In contrast, unilateral nasal obstruction presented in 82% during the late phase, whereas total nasal obstruction was present only in 41%. The most common type of late phase nasal obstruction shown by PAR was alternating nasal obstruction.

Topics: Adolescent; Adult; Allergens; Blood Proteins; Case-Control Studies; Chymases; Eosinophil Granule Proteins; Female; Follow-Up Studies; Histamine; Humans; Inflammation Mediators; Inhalation; Leukotriene C4; Male; Middle Aged; Nasal Mucosa; Nasal Obstruction; Nasal Provocation Tests; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Ribonucleases; Serine Endopeptidases; Sneezing; Tryptases

Platelet activating factor (PAF), a proinflammatory mediator synthesized through a phospholipase A2 (PLA2)-dependent reaction, is hydrolyzed into its inactive metabolite, lyso-PAF, by a specific acetylhydrolase. Previous studies have shown that allergen challenge of patients with allergic rhinitis leads to an increase of the concentrations of lyso-PAF in nasal lavage fluid (NLF), whereas PAF is detected only marginally. PAF-hydrolyzing enzymes are expected to be released on allergenic challenge, to account for the reduced concentrations of PAF in NLF. Here, we show that allergen challenge of patients with allergic rhinitis induces an increase of acetylhydrolase-like activity in NLF, which peaks within 10 minutes and returns to basal values 1 hour later. Acetylhydrolase hydrolyzed exogenous PAF with a complete loss of its ability to induce platelet aggregation. Allergen challenge also led to a parallel release of a PLA2 in nasal fluids. This enzyme preferentially hydrolyzes negatively charged phospholipids (phosphatidic acid monomethyl ester and phosphatidylgylcerol) versus phosphatidylcholine. More interestingly, the hydrolysis of phosphatidic acid monomethyl ester and phosphatidylglycerol by NLF was completely abolished by the addition of ethylenediaminetetraacetic acid which had no effect on the hydrolysis of PAF, indicating that the PLA2 secreted in nasal fluids is not involved in the degradation of PAF. Finally, our results show that allergen-induced increase in the concentrations of lyso-PAF and prostaglandin D2 occurred with a kinetic similar to that of tosyl-L-arginine-methyl-ester esterase, suggesting that mast cells are implicated in this process. Although no direct relationship was demonstrated between the absence of PAF and the increase of acetylhydrolase levels in NLF, we suggest a potential role for this enzyme in the inactivation of PAF if the latter is released in the nasal lumen.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; Allergens; Fluorometry; Humans; Nasal Lavage Fluid; Nasal Provocation Tests; Peptide Hydrolases; Phospholipases A; Phospholipases A2; Platelet Activating Factor; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Time Factors

Conjunctival provocation tests (CPTs) are used for assessing the efficacy of antiallergic treatments, but their reproducibility is not well characterized. A study was carried out to assess the reproducibility of CPTs and the release of mediators during CPTs.. Both eyes of 30 grass-pollen-allergic patients were challenged with threefold increasing concentrations of a standardized orchard grass pollen extract. The positivity of the CPT was assessed by a cumulative symptom score. The release of mediators was examined by means of histamine (radioimmunoassay), prostaglandin D2 and leukotrienes C4 and D4 (enzyme immunoassay).. There was a significant correlation between the concentrations of allergen inducing a positive CPT in both eyes (p < 0.0001, Spearman). All but one patient had a significant release of at least one mediator. After allergen CPT there was a significant release in both eyes in 13 of 20 patients for prostaglandin D2, 11 of 19 for leukotrienes C4 and D4 and 15 of 18 for histamine. The correlations between the levels of mediators released during diluent and allergen challenges in both eyes were significant for prostaglandin D2 (diluent and allergen challenges) and leukotrienes C4 and D4 (allergen challenge).. Considering the whole group of patients, CPT is reproducible in both eyes, but the results are less satisfactory when patients are examined individually.

Topics: Adult; Allergens; Conjunctiva; Conjunctivitis, Allergic; Dose-Response Relationship, Immunologic; Histamine; Humans; Male; Methods; Pollen; Prostaglandin D2; Reproducibility of Results; Rhinitis, Allergic, Seasonal; SRS-A; Tears

Lipid-derived mediators are found in nasal secretions during the early and late phase of allergic responses. To explore this early response further, concentrations of inflammatory mediators were measured along with characterization of specific cell influx during dose-dependent ragweed challenges. Ten allergic rhinitis subjects underwent two unilateral nasal lavages using 3-fold concentrations of short ragweed antigen. Low doses of ragweed (0.016-0.114 units Amb a I) did not provoke cell influx (1 of 18 challenges), whereas moderate doses (0.432-1.3 units Amb a I) induced cell influxes in 7 of 18 and at high doses in 8 of 17 challenges (3.39-11.7 units Amb a I). The differential of the cellular influx was greater than 50% neutrophils in 7 challenges; greater than 50% eosinophils in 3, and a mixed pattern in 6. There was a significant association between the dose of antigen and the level of prostaglandin D2 (PGD2), leukotrienes (LTs) C4, D4 and E4. Challenges with an eosinophilic influx tended to be associated with higher concentrations of mediators than neutrophilic influxes. Similar to the immediate skin response, the early allergic response in the nose demonstrated a cell influx with release of PGD2, LTsC4, D4 and E4. Nasal cellular inflammation therefore can occur within minutes of allergen exposure.

Topics: Allergens; Dose-Response Relationship, Immunologic; Eosinophils; Humans; Leukotriene E4; Leukotrienes; Nasal Mucosa; Neutrophils; Pollen; Prostaglandin D2; Rhinitis, Allergic, Seasonal; SRS-A

Histamine and certain cyclooxygenase products of arachidonic acid have been implicated as mediators of inflammation and are potent constrictors of human airways. Because asthma may represent manifestations of chronic inflammation of the airways, the levels of histamine and six prostanoid mediators were measured in airway fluids obtained by bronchoalveolar lavage (BAL) of 12 normal, 11 allergic rhinitic, and 15 asymptomatic, allergic asthmatic subjects. Simultaneous profiling of prostanoid mediators in individual samples was performed using gas chromatography-mass spectrometry. Levels of PGD2, 9 alpha,11 beta-PGF2 and PGF2 alpha were 12 to 22 times higher in asthmatic than in normal subjects (p less than 0.01), with concentrations in airway fluids of asthmatic subjects after correction for dilution of 3.8, 0.5, and 1.4 nanomolar, respectively. Levels of PGD2 and 9 alpha,11 beta-PGF2 were increased nearly tenfold in asthmatic subjects compared with those in rhinitic subjects (p less than 0.01), distinguishing the subjects with lower airway disease from those with another atopic condition. Histamine levels were increased fourfold in asthmatic subjects compared with those in normal subjects (p less than 0.001); however, similar increases were found in rhinitic subjects. We conclude that elevated levels of multiple mediators with potent bronchoconstricting activity are present in the airways of subjects with mild asthma, indicating that even mild disease is associated with evidence of airway inflammation. The interactions of bronchoconstricting mediators and airway inflammation may play important roles in the pathogenesis of asthma.

Topics: Adult; Asthma; Bronchoalveolar Lavage Fluid; Female; Gas Chromatography-Mass Spectrometry; Histamine; Humans; Male; Prostaglandin D2; Prostaglandins; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

Using a noninvasive skin chamber technique, we studied the in vivo development of anaphylactic reactions in 8 pollen-sensitive patients suffering from seasonal allergic rhinitis/conjunctivitis/asthma and showing positive cutaneous reactions after intradermal allergen challenge. As agonists, histamine and pollen were introduced into the skin chambers and left in contact with superficial dermis during 6 h. The release of mediators (histamine and prostaglandin [PG] D2) and the modifications in protein diffusion occurring during the immediate (30 min) and the late (6 and 24 h) cutaneous reaction phases were quantitatively analyzed. 24 h after agonist introduction, the recruitment of inflammatory cells on the superficial dermis was studied by use of Rebuck's windows. Histamine release in pollen-containing skin chambers was immediate and persisted until the 24th h despite replacement of the agonists by control medium at the 6th h. An intense PGD2 release occurred as soon as the first 30 min in chambers containing either exogenous histamine or pollen and was maintained until the 24th h. Protein diffusion induced by histamine and pollen was similar to the control one at 30 min but was intensely enhanced at the 6th h. At the 24th h, pollen-induced protein diffusion was still intense whereas that induced by histamine was analogous to the control one. 24 h after pollen challenge, numerous eosinophils were recruited on the superficial dermis but almost none were observed after control medium or histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Eosinophils; Histamine Release; Humans; Hypersensitivity, Immediate; Pollen; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Skin; Skin Window Technique; Time Factors

Studies have demonstrated that increased amounts of histamine in the airways of asthmatic patients are associated with increased airway reactivity. However, using routine bronchoalveolar lavage (BAL), histamine can be detected in only a portion of asthmatic subjects and a minority of control populations. To obtain relevant mediators from the airways in higher concentrations by avoiding the dilution inherent with a standard BAL, a technique was developed to lavage isolated airway segments of the human lung that employed a double-lumen bronchoscope and a balloon-tipped catheter. Lavage fluid obtained by this method yielded significantly higher concentrations of histamine than that obtained with routine BAL (asthmatic subjects, 2,403 +/- 633 pg/ml vs 188 +/- 42 pg/ml; rhinitis subjects, 533 +/- 187 pg/ml vs 113 +/- 53 pg/ml; normal subjects, 174 +/- 63 pg/ml vs 11 +/- 11 pg/ml). Similar findings were also noted for prostaglandin D2 (PGD2). Segmental airway lavage also resulted in higher lavage fluid concentrations of LTB, than routine BAL. Segmental airway lavage should help in studying the relationship of mast cell degranulation to airways reactivity in both asthmatic and other study populations.

Topics: Adolescent; Adult; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoscopes; Bronchoscopy; Catheterization; Histamine; Humans; Leukotriene B4; Methacholine Chloride; Methacholine Compounds; Middle Aged; Prostaglandin D2; Rhinitis, Allergic, Seasonal; Therapeutic Irrigation

Local antigen challenge in patients with respiratory allergy is associated with histamine and arachidonic acid metabolites release, both in upper and in lower respiratory airways. Raised histamine levels can be detected in nasal secretions 5 min after allergen stimulation. Increased leukotriene C4 and prostaglandin D2 concentrations persist for a longer period (respectively 20 and 30 min). Endobronchial antigen stimulation is also followed by release of histamine, leukotriene C4 and prostaglandin D2, which can be detected in bronchial lavage fluid. Elevated concentrations of these mediators can be found 5 and 15 min after challenge. Moreover, endobronchial antigen stimulation is associated with an increase in the number of bronchial epithelial cells recovered in bronchial lavage fluids.

Topics: Adult; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Chromatography, Liquid; Histamine Release; Humans; Prostaglandin D2; Respiratory Hypersensitivity; Rhinitis, Allergic, Seasonal; SRS-A

In order to assess the role of arachidonic acid metabolites in the early reaction to antigen, we challenged six allergic individuals with and without premedication with aspirin and recorded their clinical response, as indicated by number of sneezes, and measured the levels of inflammatory mediators. The early reaction to antigen was associated with increases in the levels of histamine, N-alpha-tosyl-L-arginine methyl esterase (TAME-esterase) activity, prostaglandin (PG) D2, leukotriene C4, PGE, and thromboxane. Aspirin significantly inhibited the increases in the cyclooxygenase metabolites PGE, PGD2, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane but did not affect the amount of sneezing or the levels of histamine, TAME-esterase activity, or leukotrienes. The pattern of the metabolites and their response to pretreatment with aspirin parallel the response of purified human lung mast cells, supporting the notion that the early phase of allergic rhinitis is a mast cell-dominated event.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Aspirin; Female; Histamine; Humans; Male; Nasal Provocation Tests; Peptide Hydrolases; Premedication; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Rhinitis, Allergic, Seasonal; Sneezing; SRS-A; Thromboxanes

Topics: Allergens; Histamine; Humans; Kinins; Mast Cells; Nasal Provocation Tests; Prostaglandin D2; Prostaglandins D; Rhinitis, Allergic, Seasonal; SRS-A; Tosylarginine Methyl Ester

Challenge of the nasal mucosa of allergic subjects with specific allergen induces not only the expected sneezing and rhinorrhea, but also the appearance in nasal secretions of mediators commonly associated with activation of mast cells or basophils: histamine, leukotrienes, prostaglandin D2 (PGD2), kinins, and TAME ([3H]-N-alpha-tosyl-L-arginine methyl ester)-esterase. To determine whether specific immunotherapy alters mediator release in vivo, nasal pollen challenge was used to compare 27 untreated highly sensitive ragweed (RW)-allergic subjects with 12 similarly sensitive patients receiving long-term immunotherapy (3-5 yr) with RW extract (median dose, 6 micrograms RW antigen E). The two groups were equally sensitive based on skin tests and basophil histamine release. The immunized group had a diminished response as demonstrated by (a) the treated group required higher pollen doses to excite sneezing or mediator release; (b) significantly fewer subjects in the treated group released mediators at any dose (TAME-esterase [P = 0.005], PGD2 [P = 0.04]), and (c) the treated group released 3-5-fold less mediator (TAME-esterase [P = 0.01], and histamine [P = 0.02]).

Topics: Adult; Basophils; Histamine Release; Humans; Immunotherapy; Middle Aged; Nasal Provocation Tests; Peptide Hydrolases; Pollen; Prostaglandin D2; Prostaglandins D; Rhinitis, Allergic, Seasonal; Sneezing; SRS-A

To investigate the mechanisms responsible for the late-phase response in patients with allergies, we measured four biochemical mediators (histamine, tosyl-L-arginine methyl ester [TAME]-esterase, kinin, and prostaglandin D2) in nasal secretions after nasal challenge with pollen antigen in 12 patients with allergy. Nine patients had an immediate response and a recurrence of symptoms 3 to 11 hours after challenge. The clinical symptoms during recurrence were accompanied by a second increase in levels of histamine, TAME--esterase, and kinin over base-line values, although kinin levels were lower than during the immediate response. In contrast, although the levels of prostaglandin D2 were significantly increased during the immediate response, they did not increase above base line during the late response. Rechallenge with allergen 11 hours after the initial provocation, however, was associated with reappearance of all four biochemical mediators, including prostaglandin D2. We conclude that the late response to nasal challenge with allergen is accompanied by a second increase in the concentrations of histamine and TAME--esterase but differs from the immediate response in the lack of prostaglandin D2 production and in the amount of kinin generated. Since histamine is released only by mast cells and basophils and prostaglandin D2 is not produced by basophils, we suggest that these cells are partly responsible for the late-phase response.

Topics: Adult; Allergens; Basophils; Female; Histamine Release; Humans; Kinins; Male; Mast Cells; Nasal Mucosa; Peptide Hydrolases; Prostaglandin D2; Prostaglandins D; Rhinitis, Allergic, Seasonal; Time Factors

An in vivo model of human allergic disease has been developed in which nasal challenge with antigen leads to physiologic changes, together with a release of increased amounts of inflammatory mediators into nasal secretions obtained by washing the nose with saline. In 105 experiments involving 35 subjects, only allergic subjects consistently demonstrated an increase in the concentrations of the mast cell mediator, histamine, and the putative mast cell mediators, TAME-esterase and PGD2. The release of each mediator was significantly (p less than 0.001) related to the physiologic change (sneezing). The release of each mediator also correlated significantly with the release of the other 2 mediators (p less than 0.001). This system, for the first time, clearly relates an in vivo symptom and mediator release and thus should provide an excellent tool for the further study of the allergic response and nasal pathophysiology.

Topics: Adolescent; Adult; Airway Resistance; Allergens; Bronchial Provocation Tests; Female; Histamine; Humans; Male; Nose; Peptide Hydrolases; Prostaglandin D2; Prostaglandins D; Rhinitis, Allergic, Seasonal; Sneezing