sta-2 and Asthma

The aim of this study was to elucidate the role of thromboxane A(2) (TxA(2)) on asthma-related cough in guinea pigs. Animals were immunosensitized and repeatedly challenged with ovalbumin as an antigen. Coughs were induced by the inhalation of 10(-5) M capsaicin solution for 10 min. Thromboxane synthetase (TxS) inhibitor OKY-046 and thromboxane-receptor antagonist AA-2414 significantly inhibited cough responses in repeatedly challenged animals. Inhalation of TxA(2) mimic STA-2- potentiated cough responses in normal and immunosensitized animals but not in repeatedly challenged ones. Moreover, STA-2-potentiated coughs were inhibited by administration of neurokinin-receptor antagonist FK-224. In repeatedly challenged animals, concentration of TxB(2) in airway lavage fluid, expression of TxS mRNA in tracheal epithelia, and the immunostaining intensity against TxS in mucous cells of the epithelium significantly increased compared with normal and sensitized animals. These results suggest that TxA(2) derived from mucous cells potentiated cough responses to capsaicin in allergic airway inflammation.

Topics: Animals; Asthma; Base Sequence; Bronchoalveolar Lavage Fluid; Cough; DNA, Complementary; Female; Guinea Pigs; Immunohistochemistry; Lung; Respiratory Mucosa; RNA, Messenger; Thromboxane A2; Thromboxane-A Synthase; Trachea

To investigate whether platelets are activated in asthmatics with increased release of preformed mediators and to investigate the influence of oral administration of theophylline on them.. Comparison of the intracellular free calcium concentration ([Ca2+]i) in platelets as an indicator of platelet activation, CD62P expression on platelets, and the chemokine regulated upon activation in normal T cells expressed and presumably secreted (RANTES) level in platelet-rich buffer supernatants between asthmatics and normal subjects.. The respiratory outpatient clinics, Hiroshima University, Japan.. Twenty-five normal volunteers, 19 asthmatics taking no oral drugs associated with asthma treatment (group A), and 18 asthmatics taking oral theophylline (group B).. While the resting [Ca2+]is in platelets were similar among the three groups, the [Ca2+]is in group A were significantly higher than those in normal subjects (p<0.05) and group B (p<0.01) after thrombin or 9,11-epithia-11,12-methano-thromboxane A2 (STA2) stimulation in the absence of external Ca2+. The CD62P expression level and RANTES level in group A after STA2 stimulation were significantly higher than those in normal subjects and group B (p<0.05).. We conclude that agonist-mediated activation of platelets is augmented in asthmatics resulting in enhanced release of chemokine such as RANTES, which could be suppressed by oral administration of theophylline.

Topics: Administration, Oral; Adult; Aged; Asthma; Blood Platelets; Bronchodilator Agents; Calcium; Case-Control Studies; Chemokine CCL5; Female; Gene Expression Regulation; Humans; Male; Middle Aged; P-Selectin; Platelet Activating Factor; Platelet Activation; Theophylline; Thrombin; Thromboxane A2

Membrane-derived lipid mediators have been considered to play a major role in pathogenesis of bronchial asthma. However, the importance of and the interactions among each mediator are still unclear. We examined the role of thromboxane A2 (TXA2) and platelet-activating factor (PAF) in immediate asthmatic response (IAR) and interactions between these lipid mediators in guinea pig airway in vivo using a specific TXA2 antagonist S-1452 and a specific PAF antagonist Y-24180. We confirmed the activity of each antagonist, as S-1452 and Y-24180 significantly and dose-dependently inhibited bronchoconstriction induced by respective agonist inhalation. S-1452 inhibited IAR but Y-24180 did not, indicating that TXA2 plays a major role in IAR but PAF does not. S-1452 significantly inhibited PAF-induced bronchoconstriction but Y-24180 did not inhibit synthesized TXA2 (STA2)-induced bronchoconstriction, showing that the bronchoconstrictive effect of PAF is at least in part dependent on secondarily released TXA2, but TXA2 does not induce PAF production.

Topics: Administration, Inhalation; Animals; Antigens; Asthma; Azepines; Bridged Bicyclo Compounds; Bronchoconstriction; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Guinea Pigs; Hypersensitivity; Male; Platelet Activating Factor; Receptors, Prostaglandin; Thromboxane A2; Triazoles

Effects of a thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial hyperresponsiveness induced by subthreshold concentration of aerosolized thromboxane A2 analogue (STA2) were investigated in anesthetized, artificially ventilated guinea pigs in order to examine the role of the cyclooxygenase pathway in bronchial hyperresponsiveness. Pretreatment with aerosolized OKY-046 significantly inhibited the bronchial hyperresponsiveness to histamine, but pretreatment with intravenous indomethacin showed a tendency to potentiate bronchial hyperresponsiveness. These results suggest that subthreshold concentration of thromboxane A2 contributes to bronchial hyperresponsiveness through activating the cyclooxygenase pathway including thromboxane A2 synthesis, and that the released cyclooxygenase products have an inhibitory effect on the bronchial hyperresponsiveness in guinea pigs.

Topics: Aerosols; Animals; Asthma; Bronchial Hyperreactivity; Bronchoconstriction; Dose-Response Relationship, Drug; Guinea Pigs; Indomethacin; Male; Methacrylates; Thromboxane A2

Effects of a thromboxane A2 receptor antagonist (S-1452) on bronchoconstriction induced by inhaled leukotriene C4 and a leukotriene receptor antagonist (AS-35) on bronchoconstriction caused by inhalation of a thromboxane A2 mimetic (STA2) were studied in anesthetized, artificially ventilated guinea pigs in order to examine the interaction of thromboxane A2 and leukotrienes in airways. 0.01-1.0 mu g/ml of leukotriene C4 and 0.1-1.0 mu g/ml of STA 2 inhaled from ultrasonic nebulizer developed for small animals caused dose-dependent increase of pressure at the airway opening (Pao) which is considered to be an index representing bronchial response. Pretreatment of the animals with inhaled S-1452 (0.01, 0.033 mg/ml) significantly reduced the airway responses produced by 0.01,0.033,0.1,0.33 and 1.0 mu g/ml of leukotriene C4 in a dose dependent manner. While pretreatment with inhaled AS-35 (1mg) did not affect the STA2 dose-response curve. These findings suggest that leukotriene C4 activates thromboxane A2 generation while thromboxane A2 does not influence 5-lipoxygenase pathway in the airways.

Topics: Administration, Inhalation; Animals; Asthma; Bridged Bicyclo Compounds; Bronchoconstriction; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Guinea Pigs; Histamine; Male; Pyridines; Pyrimidines; Pyrimidinones; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Prostaglandin; Receptors, Thromboxane; SRS-A; Tetrazoles; Thromboxane A2