dinoprost and Airway-Obstruction

Prostaglandin (PG)D2 is a major product of arachidonic acid metabolism in pulmonary mast cells. We therefore attempted to determine whether measurement of the stable urinary metabolite of PGD2, 9 alpha, 11 beta-PGF2, could serve as a marker of mast cell activation in the lungs. A commercially available enzyme immunoassay was validated and found to be specific and sensitive when applied to unpurified urine. There was no diurnal variation in the levels of 9 alpha, 11 beta-PGF2 in healthy volunteers. Morning baseline values of urinary 9 alpha, 11 beta-PGF2 were measured in three groups--healthy volunteers (n = 9), patients with atopic asthma (n = 14), and aspirin-intolerant patients with asthma (n = 12)--and found to be very similar, 54 +/- 9, 62 +/- 6, and 71 +/- 15 ng/mmol creatinine, respectively (means +/- SEM). Urinary excretion of 9 alpha, 11 beta-PGF2 was increased threefold immediately after allergen-induced bronchoconstriction in nine patients with atopic asthma. Bronchial challenge with inhaled lysine aspirin in eight aspirin-intolerant patients with asthma produced bronchoconstriction without extrapulmonary symptoms and was also followed by a significant increase in the urinary excretion of 9 alpha, 11 beta-PGF2. In addition, challenge with a higher dose of aspirin produced an even greater increase in urinary 9 alpha, 11 beta-PGF2, supporting dose-dependent release of PGD2 during aspirin-induced bronchoconstriction. In contrast, the postchallenge levels of urinary 9 alpha, 11 beta-PGF2 were not increased when bronchoconstriction was induced by histamine challenge in the aspirin-intolerant patients with asthma. The study confirms mast cell involvement in allergen-induced bronchoconstriction and provides novel data, which strongly support the hypothesis that pulmonary mast cells are activated during aspirin-induced airway obstruction. It is finally suggested that measurement of urinary 9 alpha, 11 beta-PGF2 with enzyme immunoassay may be used as a new noninvasive strategy to monitor mast cell activation in vivo.

Topics: Adult; Airway Obstruction; Allergens; Aspirin; Asthma; Bronchial Provocation Tests; Chromatography, High Pressure Liquid; Cross-Over Studies; Dinoprost; Double-Blind Method; Histamine; Humans; Immunoenzyme Techniques; Lysine; Mast Cells; Middle Aged; Prostaglandin D2

Cysteinyl-leukotrienes have been reported to have a primary role in the induction of nasal blockage of allergic rhinitis. However, there has been little experimental evidence that substantiates the relationship between nasal blockage severity and urinary leukotriene E4 (U-LTE4) concentration in patients with seasonal allergic rhinitis (SAR).. The concentrations of urinary mediators in 20 SAR patients were measured using an enzyme immunoassay to determine the relationship between nasal blockage severity and U-LTE4 concentration in patients with SAR.. The basal U-LTE4 concentration was significantly higher in SAR patients with severe nasal blockage than in those with mild nasal blockage and in healthy control subjects. Although U-LTE4 concentrationwas significantly higher in patients with both asthma and SAR than in SAR patients with mild nasal blockage, no significant difference in the U-LTE4 concentration between patients with both asthma and SAR and SAR patients with severe nasal blockage was found. There was a significant correlation between U-LTE4 and urinary 9alpha11beta-prostoglandin F2 (9alpha11betaPGF2) concentrations (rs = 0.51, P = 0.02) in SAR patients.. Although specific sites and cells of cysteinyl-leukotriene biosynthesis could not be determined in this study, severe nasal blockage is associated with the increased excretion level of U-LTE4.

Topics: Adolescent; Adult; Airway Obstruction; Case-Control Studies; Dinoprost; Eosinophil-Derived Neurotoxin; Female; Humans; Immunoenzyme Techniques; Leukotriene E4; Male; Middle Aged; Nasal Cavity; Osmolar Concentration; Rhinitis, Allergic, Seasonal; Ribonucleases; Severity of Illness Index

8-Epi-prostaglandin F2alpha (8-epi-PGF2alpha) is an F2-isoprostane formed mainly via noncyclooxygenase pathways in vivo. We investigated whether 8-epi-PGF2alpha has any effect on airflow obstruction and plasma exudation in vivo. Airflow obstruction was quantified by measuring lung resistance (RL) in anesthetized and ventilated guinea pigs, and plasma exudation was quantified by the Evans Blue dye method (20 mg/kg intravenously). Intratracheal instillation of 8-epi-PGF2alpha (1 nmol or 10 nmol) caused dose-related increases in RL. Furthermore, the higher dose of 8-epi-PGF2alpha produced Evans Blue dye extravasation in main bronchi and intrapulmonary airways. A prostanoid TP-receptor antagonist, BAY u3405 (1 mg/kg intravenously), abolished the airway effects of 8-epi-PGF2alpha (10 nmol). A thromboxane A2 (TxA2) synthase inhibitor, OKY-406 (30 mg/kg intravenously), significantly attenuated these effects of 8-epi-PGF2alpha (10 nmol). The level of TxB2, a stable TxA2 metabolite, increased in bronchoalveolar lavage fluid (BALF) after 8-epi-PGF2alpha instillation. We conclude that 8-epi-PGF2alpha causes airflow obstruction and plasma exudation in vivo. This effect may be mediated primarily via prostanoid TP-receptors, and a secondary generation of TxA2 may be involved in part of the airway responses in 8-epi-PGF2alpha in the guinea pig.

Topics: Airway Obstruction; Animals; Bronchoalveolar Lavage Fluid; Carbazoles; Dinoprost; Guinea Pigs; Histamine Antagonists; Male; Methacrylates; Platelet Aggregation Inhibitors; Sulfonamides; Thromboxane A2; Thromboxane B2; Vasoconstrictor Agents

1. We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, ICI-192,605 (0.5 mg kg-1, i.v.) and a selective thromboxane (Tx) synthetase inhibitor, OKY-046 (30 mg kg-1, i.v.), on airway responses induced by leukotriene D4 (LTD4; 0.2 nmol) or prostaglandin F2 alpha (PGF2 alpha; 20 nmol) instilled via the airways route to anaesthetized guinea-pigs. For a comparison, airway responses to a TxA2-mimetic, U-46619 (0.02 nmol) were also studied. We measured both lung resistance (RL) to monitor airflow obstruction, and extravasation of Evans Blue dye to quantify airway plasma exudation. 2. Instilled LTD4 into the tracheal lumen induced an immediate peak and subsequently persistent increase in RL and produced a large amount of extravasation of Evans Blue dye at all airway levels. Both ICI-192,605 and OKY-046 significantly attenuated the persistent increase in RL following the immediate response and reduced LTD4-induced extravasation of Evans Blue dye in the trachea and proximal intrapulmonary airway. Instilled LTD4 produced significant increases in immunoreactive TxB2 in bronchoalveolar lavage fluid obtained 1.5 min after instillation of LTD4. 3. Instilled PGF2 alpha into the tracheal lumen induced an immediate increase in RL which peaked at approximately 15 s. We also observed a delayed sustained increase in RL, reaching a second peak at approximately 4 min. PGF2 alpha produced small but significant increases in the amount of Evans Blue dye at all airway levels. As with PGF2 alpha, instillation of U-46619 produced a biphasic increase in RL and extravasation of Evans Blue dye. The potency of PGF2a, in inducing these airway responses was about 1000 times less than U-46619. ICI-192,605 abolished both the immediate and the delayed increase in RL after PGF2a, and also blocked PGF2a,-induced extravasation of Evans Blue dye. However, OKY-046 had no inhibitory effects on these responses.4. We conclude that airflow obstruction and airway plasma exudation induced by instilled LTD4 is, in part, mediated via TxA2 generation and subsequent activation of TP-receptors. On the other hand,instilled PGF2a, while inducing similar responses, does so primarily by direct activation of TP receptors,rather than via TxA2 generation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Obstruction; Airway Resistance; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Capillary Permeability; Dinoprost; Dioxanes; Evans Blue; Exudates and Transudates; Guinea Pigs; In Vitro Techniques; Leukotriene D4; Male; Methacrylates; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

Topics: Airway Obstruction; Dinoprost; Humans; Infant

Plasma concentrations of a stable prostaglandin F2 alpha metabolite were measured by radioimmunoassay during and after recovery from acute airway obstruction in 15 infants. Mean (SEM) metabolite concentrations (ng/l) in plasma obtained both before (1033 (418)) and after (1470 (413)) initial treatment for airway obstruction were significantly higher than those obtained from the same subjects after resolution of the obstruction--25.5 (6.6)--and those obtained from two comparison groups. Infants positive for respiratory syncytial virus (mean 1122 (227)) had significantly higher concentrations than those who were negative (207.6 (46)). Additionally, seven subjects with a history of recurrent wheezing after resolution of airway obstruction had a significantly higher mean level (3500 (1400)) during attacks of airway obstruction than those without (600 (100)). These data suggest that prostaglandin F2 alpha mediates respiratory inflammation in airway obstruction and that trials of specific anti-inflammatory agents for the treatment of airway obstruction may be warranted.

Topics: Airway Obstruction; Dinoprost; Humans; Infant; Nose; Respiratory Sounds; Respiratory Syncytial Viruses

In three series of experiments, aerosols of acetylcholine, histamine, and Ascaris were administered in a maximal concentration before and after bilateral vagus transection. Vagotomy induced a clear reduction of the dynamic elastance increase by maintaining a constant breath volume. The persisting reaction of the dynamic elastance after vagotomy depends on the intensity of the reaction before vagus transection. Acetylcholine induced the largest reaction. Changes in epinephrine and norepinephrine were found to be variable, but an increase related to dynamic elastance increase could be assumed. Acetylcholine induced a maximal increase in thromboxane B2, and Ascaris induced preferentially a maximal increase in the prostaglandin F2 alpha metabolite 15-Keto-13, 14-dihydro-PGF2 alpha. Vagotomy showed no influence on changes of thromboxane B2, prostaglandin F2 alpha metabolite, or histamine in arterial plasma. The variability in changes of these metabolites may be the cause of the clinical differences in obstructive airway diseases.

Topics: Acetylcholine; Aerosols; Airway Obstruction; Allergens; Animals; Ascaris; Dinoprost; Dogs; Elasticity; Epinephrine; Histamine; Lung; Norepinephrine; Prostaglandins F; Thromboxane B2; Vagus Nerve

Plasma concentrations of prostaglandins E2 (PGE2) and F2a (PGF 2a) are studied in venous and arterial blood in 14 healthy subjects and 32 asthmatic patients. In the asthmatic patients we found: (1) a good correlation between PGE2 concentration in venous blood and the seriousness of the airway obstruction; (2) a good correlation between PGE2 and PGF2a in the arterial blood, but not in the venous blood; (3) a decrease in the arterial concentrations of PGE2 and PGF2a after fenoterol-induced bronchodilatation, but the variations of PGE2 and PGF2a still correlate. None of these results were obtained in normal subjects. It seems that the asthmatic allergic patient has a disorder of the metabolism of prostaglandins in the lungs; however, the results obtained do not allow us to say if it is a causal condition or a metabolic consequence of the bronchospasm. Concerning the venous blood, there could be an increase in the peripheral production of PGE2 which might result from the hypoxemia following airway obstruction.

Topics: Adolescent; Adult; Airway Obstruction; Arteries; Asthma; Dinoprost; Dinoprostone; Fenoterol; Humans; Lung; Middle Aged; Prostaglandins E; Prostaglandins F; Veins