thromboxane-b2 and Bronchial-Spasm

To determine if platelet activation occurs after allergen inhalation in atopic asthmatics, we measured two urinary metabolites of the principal cyclooxygenase product of platelets, thromboxane A2 (TxA2), using the sensitive and specific technique of gas chromatography-negative ion, chemical ionization-mass spectrometry. Seven atopic asthmatics underwent allergen challenge after low dose aspirin to suppress platelet thromboxane generation and on placebo days. On placebo days, the urinary levels of 2,3-dinor-TxB2 increased from 76 +/- 22 pg/mg creatinine to 216 +/- 95 after allergen, and 11-dehydro-TxB2 from 396 +/- 98 to 627 +/- 137 (p less than 0.05). Low dose aspirin suppressed excretion of urinary thromboxane metabolites and prevented the rise after allergen inhalation without altering the bronchoconstriction. Excretion of 2,3-dinor-6-keto-PGF1 alpha, a metabolite of prostacyclin, was unaltered by this aspirin regimen. We conclude that platelets are activated after allergen challenge, but that platelet-derived TxA2 is not important in the early bronchoconstrictor response.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Allergens; Aspirin; Blood Platelets; Bronchial Spasm; Clinical Trials as Topic; Cyclooxygenase Inhibitors; Female; Forced Expiratory Volume; Gas Chromatography-Mass Spectrometry; Humans; Male; Placebos; Platelet Activation; Thromboxane A2; Thromboxane B2

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

A novel chemical compound, DT-TX 30 SE (E-6-(4-2-(4-chlorobenzenesulphonylamino)-ethyl)phenyl)-6-(3-pyrid yl)- hex-5-enoic acid), was studied in various models of guinea pig pulmonary function. The compound was a potent inhibitor (ED50 0.019 mg/kg, i.v.) of bronchospasm induced by the thromboxane receptor agonist U-46619, indicating thromboxane receptor antagonism. At even lower doses (ED50 0.0036 mg/kg, i.v.), it blocked arachidonic acid-induced bronchospasm. Interpretation of the latter results as evidence for additional thromboxane synthetase inhibitory activity was supported by the inhibition of arachidonic acid- or bradykinin-induced thromboxane B2 production in an isolated lung preparation, although prostaglandin E2 and prostaglandin 6-oxo-F(1 alpha) production measured at the same time were not inhibited. The potency of DT-TX 30 SE was compared with thromboxane receptor antagonists and synthetase inhibitors described in the literature. As a receptor antagonist, DT-TX 30 SE was significantly more potent than BM 13505 and BM 13177 (assessed by antagonism of U-46619-induced bronchospasm), but less potent than SQ 29548, while as a thromboxane synthetase inhibitor, it was significantly more potent than OKY 046 and UK 37248 as assessed by antagonism of arachidonic acid-induced bronchospasm or (OKY 046) inhibition of thromboxane production in isolated lung. The compound was active by the oral route as shown by its ability, at 10 mg/kg, p.o., to significantly reduce the immediate allergic response of sensitized guinea pigs to an ovalbumin aerosol.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acid; Bronchial Spasm; Dinoprostone; Enzyme Inhibitors; Fatty Acids, Unsaturated; Guinea Pigs; Lung; Male; Prostaglandin Endoperoxides, Synthetic; Pyridines; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Aspirin and nonsteroidal antiinflammatory drugs induce bronchospastic reactions in patients with aspirin-sensitive respiratory disease. Although the mechanism of this reaction is unknown, all drugs that induce the respiratory reaction also inhibit the cyclooxygenase enzyme. The ensuing changes in arachidonate metabolism are presumed to play a role in the pathogenesis of the reaction. We measured generation of leukotrienes and thromboxane by calcium ionophore stimulated blood monocytes. Before aspirin challenge, monocytes released significantly more thromboxane B2 in patients with aspirin sensitivity than in patients without aspirin sensitivity or in healthy control subjects (p < 0.02). During aspirin-induced bronchospasm, release of leukotriene B4 increased significantly (45.5%, p = 0.018), whereas release of thromboxane B2 decreased (-46.9%, p = 0.028). Two hours after ingestion of 60 mg aspirin, normal monocyte release of thromboxane B2 did not drop, whereas leukotriene B4 release increased. Monocytes formed only minimal amounts of leukotriene C4. We conclude that the profile of released eicosanoids from aspirin-sensitive monocytes is distinct from non-aspirin-sensitive subjects, and that these differences could contribute to the development of bronchospasm after aspirin ingestion.

Topics: Administration, Oral; Adult; Arachidonic Acid; Aspirin; Asthma; Bronchial Spasm; Calcimycin; Eicosanoids; Female; Humans; Leukotriene B4; Male; Middle Aged; Monocytes; Thromboxane B2

The development of an allergic bronchoconstriction model in rats is described. In actively sensitized Donryu strain rats, there was a remarkable biphasic increase in airway resistance within 10 min after antigen challenge on day 9 to day 21. The increase in airway resistance, correlated with the IgE titer and the dose of antigen, was inhibited by disodium cromoglycate (DSCG) or by aminophylline. This bronchoconstriction was remarkably blocked by methysergide (25 and 100 micrograms/kg) while pyrilamine inhibited it partially at the same dose. Serotonin (greater than 30 micrograms/kg) but not histamine (less than 1,000 micrograms/kg) induced a bronchoconstriction. FPL-55712 (1,10 mg/kg) inhibited it significantly. The content of thromboxane B2 (TxB2) in plasma increased during the bronchoconstriction while the content of peptide-leukotrienes (p-LTs) in plasma did not increase significantly. OKY-046 inhibited not only allergic bronchoconstriction but also the increase in TxB2 levels in plasma. The late phase of the bronchoconstriction was more susceptible to OKY-046. In conclusion, this model seems to be useful for the screening of antiasthma drugs because of a relationship with the dose of antigen, IgE titer and the susceptibility to an antiallergic drug or a bronchodilator. It is demonstrated that the major part of this allergic bronchoconstriction depends on serotonin, and it is also suggested that thromboxane A2 may play an important role in the late phase of the bronchoconstriction.

Topics: Airway Resistance; Allergens; Aminophylline; Animals; Bronchial Spasm; Chromones; Cromolyn Sodium; Dose-Response Relationship, Immunologic; Histamine; Hypersensitivity; Leukotrienes; Male; Methacrylates; Methysergide; Pyrilamine; Rats; Rats, Inbred Strains; Serotonin; Thromboxane B2; Time Factors

Sulfidopeptide leukotrienes (LTs) C4, D4 and E4 are important mediators in the pathophysiology of bronchial asthma. Sch 37224, 1-(1,2-dihydro-4-hydroxy-2-oxo-1-phenyl-1,8-naphthyridin-3-yl) pyrrolidinium, hydroxide inner salt, has been found to inhibit the formation of these autocoids. Although Sch 37224 did not inhibit 5-lipoxygenase, cyclooxygenase or phospholipase A2, it inhibited LTD4 and thromboxane B2 release by anaphylactic guinea pig lung (IC40 = 3.9 and 1.9 microM, respectively). At 5 microM Sch 37224 also inhibited superoxide anion radical generation from activated human polymorphonuclear neutrophilic leukocytes. When administered p.o. to guinea pigs, Sch 37224 decreased a LT-mediated allergic bronchospasm (ED40 = 1.1 mg/kg) for 6 hr and did not exhibit tolerance. In addition to its activities in allergen-induced bronchospasm in guinea pigs, Sch 37224 also inhibited hyperventilation-induced bronchospasm in guinea pigs at 0.5 to 5 mg/kg and anaphylactic bronchospasm in rats at 0.1 to 10 mg/kg. Sch 37224 was weak or ineffective as an antagonist of histamine, methacholine, serotonin, LTC4 or platelet activating factor induced bronchospasms in guinea pigs. Also, Sch 37224 was not a bronchodilator or calcium influx blocker and had only weak relaxant activity on guinea pig trachea in vitro (IC40 = 51 microM). Sch 37224 is, therefore, a potential antiallergic agent that inhibits LT release. It is p.o. effective in animal models of allergic and nonallergic-mediated bronchospasms.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Bronchi; Bronchial Spasm; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Hypersensitivity; In Vitro Techniques; Leukotriene Antagonists; Leukotrienes; Male; Naphthyridines; Rats; Thromboxane B2

In order to investigate whether bronchopulmonary hyperresponsiveness represents a unique property of sensitized lungs, we examined the responses of lungs from either actively sensitized, passively sensitized, or nonsensitized (control) guinea pigs to in vitro bronchoconstriction (BC) and release of thromboxane (TX) B2, 6-keto-PGF1 alpha, and histamine induced by platelet-activating factor (PAF-acether) or leukotriene (LT) D4. Guinea pigs were actively sensitized with 10 micrograms of either ovalbumin or Dermatophagoides farinae extract in AI(OH)3 injected intraperitoneally twice at a 2-wk interval. Seven days after the second injection (booster injection), the lungs were removed, ventilated, and perfused via the pulmonary artery with Krebs solution containing 2.5 g/L bovine serum albumin. In lungs from actively sensitized animals, BC was induced by significantly lower doses of PAF-acether and LTD4 than those required to elicit the same response in control preparations. In addition, sensitized lungs released more TxB2, 6-keto-PGF1 alpha, and histamine in response to PAF-acether and LTD4 than did control lungs. Increased mediator release was also observed upon challenge of lungs from actively sensitized animals with arachidonic acid and histamine. Lungs from guinea pigs passively sensitized with serum from actively sensitized animals did not exhibit increased responsiveness to PAF-acether as compared to control lungs. The hyperresponsiveness induced after booster injection of the antigen occurred concomitantly with an increase in the homocytotropic antibody titer (as measured by passive cutaneous anaphylaxis) and persisted for 3 months after sensitization, when the levels of circulating antibodies and lung response to antigen challenge returned to control values.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchial Spasm; Capillary Permeability; Female; Guinea Pigs; Histamine; Immunization; Immunization, Secondary; Kinetics; Lung; Male; Ovalbumin; Perfusion; Platelet Activating Factor; Pulmonary Circulation; Respiratory Hypersensitivity; SRS-A; Thromboxane B2

We examined the role of cyclooxygenase-derived metabolites and epithelial cells in airflow-induced bronchospasm. Male dogs were anesthetized and collateral system resistance (Rcs) was measured with the wedged-bronchoscope technique. A 2-min high flow challenge with dry air in nine animals produced a mean increase in Rcs of 69 +/- 13% (SE). After treatment with indomethacin (5 mg/kg), the response was significantly attenuated; Rcs increased only 40 +/- 8%. Bronchoalveolar lavage performed 5 min after a dry air challenge yielded fluid with greater concentrations of prostaglandin D2 (PGD2) and thromboxane B2 than samples from unchallenged segments. Challenge with humidified air produced a smaller physiological response than did challenge with dry air. Lavage samples obtained after dry challenge had greater concentrations of PGD2 than samples taken after challenge with humidified air. After dry air challenge, epithelial cells in lavage fluid were increased by 454 and 515% when compared with control and humidified air challenge, respectively. Significant correlations were found between epithelial cell number and PGD2 recovered in lavage fluid after dry air challenges. We conclude that both epithelial cells and prostaglandins play an important role in peripheral lung responses to dry air.

Topics: Airway Resistance; Animals; Bronchial Spasm; Cell Count; Cyclooxygenase Inhibitors; Dogs; Epithelial Cells; Epithelium; Humidity; Male; Osmolar Concentration; Prostaglandins D; Pulmonary Ventilation; Respiratory Physiological Phenomena; Respiratory System; Thromboxane B2

In this paper we report an inhibitory effect of (-)-baclofen on many models of bronchial hyperreactivity both in vivo and in vitro. (-)-Baclofen protects guinea-pigs from the anaphylactic bronchospasm induced in sensitized animals by an ovalbumin aerosol and from that induced by aerosols of histamine and PGF2 alpha. Moreover (-)-baclofen reduces the TXA2 and TXB2 output induced by ovalbumin from isolated sensitized guinea-pig lungs. On the other hand (-)-baclofen does not show antihistaminic, anticholinergic or antiprostaglandinic action on isolated tracheal preparations. It is concluded that baclofen can provide protection from bronchial hyperreactivity possibly through a modulation of autonomic nervous system activity.

Topics: Acetylcholine; Anaphylaxis; Animals; Baclofen; Bronchial Spasm; Dinoprost; Guinea Pigs; Histamine Antagonists; Lung; Male; Prostaglandins F; Thromboxane A2; Thromboxane B2