prostaglandin-d2 and Bronchial-Spasm

The immediate and late asthmatic reactions provoked by inhaled allergens have provided useful models enabling the dissection of individual inflammatory cells and their mediators that may contribute to the pathogenesis of asthma. The immediate reaction is considered to be mast cell-mediated on the basis that about 50% of the response is inhibitable by potent and selective H1-receptor antagonists such as terfenadine and astemizole. Additional inhibition (approximately 30%) by the potent cyclooxygenase inhibitor flurbiprofen implies an important role for prostanoids in the immediate response, the most likely mast cell-derived product being prostaglandin (PG) D2. In man, PGD2 is selectively metabolised to 9 alpha 11 beta-PGF2, a unique prostaglandin which shares with PGD2 contractile properties on guinea-pig and human airways smooth muscle. The inability of piriprost, a potent leukotriene synthesis inhibitor, to influence the allergen-provoked immediate reaction raises the possibility that sulphidopeptide leukotrienes play a minor role in this response. The late asthmatic reaction is considered to resemble clinical asthma since it is accompanied by increased responsiveness of the airways to a wide range of stimuli. The late reaction in man is inhibited by nedocromil sodium (4 mg) but only marginally attenuated by salbutamol (200 micrograms) if both drugs are administered prior to allergen challenge. Since salbutamol, in the dose administered, is a potent mast cell-stabilising agent, these findings must question the obligatory role of mast cell mediator release in the pathogenesis of the late response.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Allergens; Animals; Asthma; Bronchi; Bronchial Spasm; Bronchodilator Agents; Child; Eosinophils; Epithelium; Exocytosis; Guinea Pigs; Humans; Hypersensitivity, Immediate; Inflammation; Mast Cells; Prostaglandin Antagonists; Prostaglandin D2; Prostaglandins D; SRS-A

Prostaglandin D2 (PGD2) causes cough and levels are increased in asthma suggesting that it may contribute to symptoms. Although the prostaglandin D2 receptor 2 (DP2) is a target for numerous drug discovery programmes little is known about the actions of PGD2 on sensory nerves and cough. We used human and guinea pig bioassays, in vivo electrophysiology and a guinea pig conscious cough model to assess the effect of prostaglandin D2 receptor (DP1), DP2 and thromboxane receptor antagonism on PGD2 responses. PGD2 caused cough in a conscious guinea pig model and an increase in calcium in airway jugular ganglia. Using pharmacology and receptor-deficient mice we showed that the DP1 receptor mediates sensory nerve activation in mouse, guinea pig and human vagal afferents. In vivo, PGD2 and a DP1 receptor agonist, but not a DP2 receptor agonist, activated single airway C-fibres. Interestingly, activation of DP2 inhibited sensory nerve firing to capsaicin in vitro and in vivo. The DP1 receptor could be a therapeutic target for symptoms associated with asthma. Where endogenous PGD2 levels are elevated, loss of DP2 receptor-mediated inhibition of sensory nerves may lead to an increase in vagally associated symptoms and the potential for such adverse effects should be investigated in clinical studies with DP2 antagonists.

Topics: Administration, Inhalation; Animals; Bronchial Hyperreactivity; Bronchial Spasm; Capsaicin; Cells, Cultured; Cough; Disease Models, Animal; DNA-Binding Proteins; Guinea Pigs; Humans; Indoles; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Thromboxane; Sensitivity and Specificity; Tissue Culture Techniques; Transcription Factor DP1; Transcription Factors; Vagus Nerve

Aspirin causes bronchospasm in patients with aspirin exacerbated respiratory disease (AERD). The contribution of mast cells to the increased cysteinyl-leucotrienes (cys-LTs) detected in AERD patients is however not defined.. Effects of prostaglandin (PG) E(2) and inhibitors of cyclooxygenase (COX) and lipoxygenase (LO) pathways on mediator release from cultured mast cells of normal subjects, aspirin tolerant asthma (ATA) and AERD patients were compared to better define the role of mast cells in AERD.. Mast cells were cultured from peripheral blood progenitors and were activated by anti-IgE. Histamine, PGD(2) and cys-LTs released were then determined.. Basal release of all three mediators was similar in all subjects. Although the release of all three mediators was increased by anti-IgE, mast cells from AERD patients produced significantly more cys-LTs (6.9 +/- 2.0 ng/10(6) cells) than normal and ATA subjects (2.3 +/- 0.8 and 1.7 +/- 0.5 ng/10(6) cells, respectively). While COX and LO pathway inhibitors did not affect anti-IgE induced histamine release, they significantly suppressed the production of PGD(2) and cys-LTs, respectively, in all patients. PGE(2) significantly enhanced anti-IgE induced histamine and PGD(2) release from mast cells of normal subjects but not those of ATA and AERD patients. In contrast, PGE(2) suppressed only anti-IgE induced cys-LTs release from mast cells of AERD patients.. We speculate that overproduction of cys-LTs is unique to mast cells of AERD patients and is particularly sensitive to suppression by PGE(2). Consequently reduction of PGE(2) production by aspirin removes this endogenous control of cys-LTs overproduction, resulting in asthma attack.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Anti-Idiotypic; Aspirin; Bronchial Spasm; Cells, Cultured; Cysteine; Dinoprostone; Female; Histamine; Humans; Immunoglobulin E; Leukotrienes; Male; Mast Cells; Prostaglandin D2

Adenosine causes bronchoconstriction in asthmatic patients, and it is also accepted that adenosine influences histamine release from activated human mast cells and basophils in vitro.. In this study we tested the hypothesis that adenosine potentiates both the airway narrowing and the release of bronchoconstrictor mediators induced by ovalbumin challenge in sensitized guinea pigs.. After ovalbumin sensitization, 4 groups were studied: control group, adenosine group (ADO), ovalbumin group (OA), and adenosine plus ovalbumin group (ADO + OA). Changes in airway resistance were assessed from continuously recorded pulmonary insuffilation pressure (PIP). The concentration of histamine, PGD2, and thromboxane B2 were determined from bronchoalveolar lavage fluids.. Adenosine alone (6 mg/kg intravenously) did not influence baseline values of PIP and the mediator concentrations; however, ovalbumin (10 mg/kg intravenously) increased both the PIP and the levels of the measured mediators compared with the control and ADO groups. When ovalbumin challenge was preceded by adenosine administration, both PIP and mediator levels were significantly enhanced compared with values obtained after simple ovalbumin provocation (ADO + OA vs OA: P <.05).. These results suggest that adenosine potentiates the airway narrowing induced by ovalbumin challenge and that this effect may develop through facilitation of the release of bronchoconstrictor mediators during the immediate airway response.

Topics: Adenosine; Animals; Bronchial Provocation Tests; Bronchial Spasm; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Guinea Pigs; Histamine; Humans; Ovalbumin; Prostaglandin D2; Thromboxane B2

In summary, mast cell activation is associated with the release of chemotactic factors, enzymes, proteoglycans, and vasoactive mediators. The vasoactive mediators include the leukotrienes, prostaglandin PGD2, adenosine, PAF, and histamine. Their effects are associated with an early phase reaction. This early reaction in the airways is manifested by cough, wheeze, mucous secretion, and a short-lived bronchospastic response. The release of chemotactic factors perhaps including PAF, eosinophil-directed and neutrophil-directed mediators would be associated with the influx into the airway of a variety of leukocytes although neutrophils and eosinophils predominate. The eosinophil contains a variety of toxic materials including a major basic protein known to kill tracheal epithelial cells. The eosinophil also generates PAF and leukotrienes. It could, therefore, be responsible for a self-sustaining tissue damaging inflammatory infiltrate. And finally, there are the neutral protease enzymes whose function remains unknown. It is tempting to speculate that the vasoactive mediators cause an early phase reaction while the enzymes and chemotactic factors set up the inflammation associated with a late phase response. The clinical pertinence to this has been demonstrated by researchers who studied nonspecific bronchial reactivity in patients who have early phase reactions only as compared with those who have both early and late phase reactions to antigen bronchoprovocation. These individuals with only an early phase reaction following antigen bronchoprovocation have a lesser degree of sensitivity to histamine, ie, it requires more histamine to cause bronchoconstriction, and there is no change in their histamine threshold after their early phase response.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Airway Resistance; Allergens; Asthma; Biopsy; Bronchi; Bronchial Spasm; Humans; Lung; Mast Cells; Neuropeptides; Platelet Activating Factor; Prostaglandin D2; Prostaglandins D; Respiratory System; Skin; SRS-A

Topics: Adenosine; Allergens; Asthma; Bronchi; Bronchial Spasm; Humans; Mast Cells; Prostaglandin D2; Prostaglandins D; Skin

1 A threshold dose of Prostaglandin D2 (PGD2) (0.5 microgram/kg i.v.), which did not modify the basal values of airway resistance, potentiated the acetylcholine induced bronchospasm in anaesthetized guinea-pigs. 2 beta-adrenoreceptors blockade induced by propranolol enhanced the positive interaction between PGD2 and acetylcholine in the pulmonary dynamics. 3 Active sensitization of guinea-pigs by ovalbumin increased the pulmonary PGD2-acetylcholine interaction and the phenomenon was sustained during the time. 4 The inability of PGD2 to potentiate histamine-induced bronchoconstriction suggests a specificity for the interaction.

Topics: Acetylcholine; Airway Resistance; Animals; Bronchial Spasm; Drug Synergism; Guinea Pigs; Histamine; Male; Ovalbumin; Propranolol; Prostaglandin D2; Prostaglandins D; Respiratory Hypersensitivity

Topics: Adult; Allergens; Asthma; Bronchial Spasm; Humans; Hypersensitivity; Male; Prostaglandin D2; Prostaglandins D; Pulmonary Alveoli; Skin Tests