thromboxane-a2 and Airway-Obstruction

Airway obstruction after antigen challenge is not always observed in patients with allergic asthma, even if they develop hyperresponsiveness. A similar event is observed in our guinea pig model of allergic asthma. Our aim was to study this phenomenon.. Sensitized guinea pigs were challenged with ovalbumin (OVA) 3 times every 10 days. Animals were divided into 2 groups: (1) Guinea pigs exhibiting airway obstruction after antigen challenge (R = responders), and (2) guinea pigs lacking airway obstruction response (NR = nonresponders). After the third antigen challenge, antigen-induced airway hyperresponsiveness (AI-AHR), serum OVA-specific immunoglobulins, bronchoalveolar lavage fluid (BALF) inflammatory cells, histamine, cysteinyl leukotrienes and thromboxane A2 (TxA2) BALF levels, and in vitro tracheal contraction induced by contractile mediators and OVA were evaluated.. R group consistently displayed a transient antigen-induced airway obstruction (AI-AO) as well as AI-AHR, high T×A2, histamine, OVA-IgG1, OVA-IgE and OVA-IgA levels, and intense granulocyte infiltration. NR group displayed no AI-AO and no changes in BALF measurements; nevertheless, AI-AHR and elevated OVA-IgG1 and OVA-IgA levels were observed. In all groups, histamine, TxA2 and leukotriene D4 induced a similar contraction. Tracheal OVA-induced contraction was observed only in R group. AI-AHR magnitude showed a direct association with OVA-IgG1 and OVA-IgA levels. The extent of AI-AO correlated directly with OVA-IgE and inversely with OVA-IgA levels.. Our data suggest that TxA2 and histamine participate in AI-AO likely through an IgE mechanism. AI-AHR might occur independently of AI-AO, contractile mediators release, and airway inflammatory cell infiltration, but IgA and IgG1 seem to be involved.

Topics: Airway Obstruction; Animals; Antigens; Asthma; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Guinea Pigs; Histamine; Humans; Immunization; Immunoglobulins; Leukotriene D4; Male; Ovalbumin; Respiratory Hypersensitivity; Thromboxane A2

U-46619, a thromboxane A(2) (TXA(2)) mimetic, is shown to cause airway microvascular leakage, although the effects is weak when comparing with that to induce bronchoconstriction in guinea pigs.. In order to know the airway effect of TXA(2) more accurately, we have examined the effects of STA(2), a TXA(2) mimetic with higher affinity to TXA(2) (TP) receptors than U-46619, to induce airway microvascular leakage and airflow obstruction.. Anesthetized and ventilated guinea pigs were i.v. given STA(2) (3-30 nmol/kg) or U-46619 (3-100 nmol/kg) 1 min after i.v. Evans blue dye. STA(2)- and U-46619-induced increases in lung resistance (R(L)) was measured for 6 min. The amount of extravasated Evans blue dye in the lower airways was, then, examined as an index of leakage. In selected animals, specific TP receptor antagonists (10 microg/kg S-1452 or 10 mg/kg ONO-3708) were pretreated i.v.. Both STA(2) and U-46619 induced significant increases in leakage and airflow obstruction. However, STA(2) induced a slow and significantly less increase in R(L) but caused a significantly greater increase in extravasation of Evans blue dye compared to U-46619. Specific TP receptor antagonists completely abolished both airway effects induced by STA(2) and U-46619.. Our present results have supported a possibility that TXA(2) induces microvascular leakage as well as bronchoconstriction in the airways.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Obstruction; Airway Resistance; Animals; Blood Pressure; Bridged Bicyclo Compounds; Capillary Permeability; Dose-Response Relationship, Drug; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Fatty Acids, Monounsaturated; Guinea Pigs; Lung; Male; Platelet Aggregation Inhibitors; Thromboxane A2; Time Factors; Vasoconstrictor Agents

The contributions of histamine, cysteinyl leukotrienes (CysLTs) and thromboxane A2 (TXA2) to the asthmatic responses and the magnitudes of blood and lung eosinophilia at acute and chronic stages of our asthmatic model were comparatively determined. Guinea pigs were alternately sensitized/challenged by inhalation with ovalbumin+Al(OH)3 and ovalbumin, once every 2 weeks. Effects of mepyramine, pranlukast (a CysLT antagonist) and seratrodast (a TXA2 antagonist) on the early (EAR) and/or the late asthmatic response (LAR) were assessed at the second and fourth antigen challenges. The second challenge caused EAR but not LAR. Although the EAR was decreased at the fourth challenge, a substantial LAR was seen. Both mepyramine and seratrodast inhibited the EAR at the second challenge by approximately 50%. However, at the fourth challenge, these drugs did not inhibit the EAR. The LAR at the fourth challenge was attenuated by pranlukast and seratrodast by 45% and 40%, respectively. Both the blood and lung eosinophilia were modestly and markedly induced 5 h after the second and fourth challenges, respectively. These results strongly suggest that repetition of antigen challenge induces quantitative alterations of chemical mediators participating in the asthmatic responses and a change of the body state under which eosinophils exhibit enhanced migratory activities.

Topics: Administration, Inhalation; Airway Obstruction; Aluminum Hydroxide; Animals; Antigens; Asthma; Benzoquinones; Chromones; Eosinophilia; Guinea Pigs; Heptanoic Acids; Histamine H1 Antagonists; Leukotriene Antagonists; Lung; Male; Ovalbumin; Prostaglandin Antagonists; Pyrilamine; Thromboxane A2

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

1. The mechanisms behind bradykinin-induced effects in the airways are considered to be largely indirect. The role of cholinergic nerves and eicosanoids, and their relationship in these mechanisms were investigated in guinea-pigs. 2. The role of cholinergic nerves was studied in animals given atropine (1 mg kg-1, i.v.), hexamethonium (2 mg kg-1, i.v.), or vagotomized. To study the role of eicosanoids, animals were pretreated with a thromboxane A2 (TxA2) receptor antagonist (ICI 192,605; 10(-6) mol kg-1, i.v.) or with a leukotriene (LT) receptor C4/D4/E4 antagonist (ICI 198,615; 10(-6) mol kg-1, i.v.). 3. After pretreatment with a drug, bradykinin (150 nmol) was instilled into the tracheal lumen. We measured both airway insufflation pressure (Pi), to assess airway narrowing, and the content of Evans blue dye in airway tissue, to assess plasma exudation. 4. Bradykinin instillation into the trachea caused an increase in Pi and extravasation of Evans blue dye. The increase in Pi was significantly attenuated by atropine or the TxA2 receptor antagonist, but not by hexamethonium, vagotomy or the LT receptor antagonist. 5. The bradykinin-induced exudation of Evans blue dye was significantly attenuated in the intrapulmonary airways by the TxA2 receptor antagonist, but not by atropine, hexamethonium, cervical vagotomy or the LT receptor antagonist. 6. A thromboxane-mimetic U-46619 (20 nmol kg-1, i.v. or 10 nmol intratracheally), caused both an increase in Pi and extravasation of Evans blue dye at all airway levels. Atropine pretreatment slightly attenuated the peak Pi after the intratracheal administration of U-46619, but not after i.v. administration. 7. We conclude that peripheral cholinergic nerves are involved in bradykinin-induced airflow obstruction but not plasma exudation, and that TxA2 is involved in both airflow obstruction and airway plasma exudation induced by bradykinin given via the airway route. TxA2-induced airflow obstruction is mediated only to a minor degree, via the release of acetylcholine in the airways.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Airway Obstruction; Animals; Blood Pressure; Bradykinin; Eicosanoids; Evans Blue; Exudates and Transudates; Guinea Pigs; In Vitro Techniques; Leukotriene Antagonists; Male; Parasympathetic Nervous System; Parasympathomimetics; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Respiratory Mechanics; Respiratory System; Thromboxane A2; Vagotomy; Vasoconstrictor Agents

The actions of LY255283, a leukotriene (LT) B4 receptor antagonist, were examined on guinea pig lung. LTB4 and LY255283 displaced [3H]LTB4 from its binding site on lung membranes with pKi values of 9.9 and 7.0, respectively. In the functional correlate of the binding studies, LY255283 competitively reduced contractile responses of lung parenchyma to LTB4 (pA2 = 7.2). LTB4 produced airway obstruction which was reduced by LY255283 administered i.v. (ED50 = 2.8 mg/kg) or orally (ED50 = 11.0 mg/kg). Contractile responses to histamine, LTD4 and the thromboxane mimetic, U46619, were not reduced by LY255283. The compound also did not inhibit cyclooxygenase or 5-lipoxygenase enzymes. We conclude that LY255283 selectively antagonized pharmacologic responses to LTB4 on lung tissue and appears to be a useful tool to investigate the role of LTB4 in pulmonary disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Obstruction; Analgesics; Animals; Dinoprostone; Guinea Pigs; In Vitro Techniques; Leukotriene B4; Lung; Lung Volume Measurements; Male; Membranes; Muscle Contraction; Prostaglandin Endoperoxides, Synthetic; Pulmonary Gas Exchange; Radioligand Assay; Receptors, Immunologic; Receptors, Leukotriene B4; Tetrazoles; Thromboxane A2

Conscious guinea pigs that were briefly exposed to an aerosol of A23187 developed a prolonged airway constrictive response that lasted at least 60 min. Cumulative i.v. doses of various drugs were given and reversal of dynamic compliance (Cdyn) examined. After the final dose of each agent, the animals were killed and excised lung gas volumes, i.e., pulmonary gas trapping, measured. Salbutamol, a beta-2 adrenoceptor agonist; phenidone, a 5-lipoxygenase inhibitor; aminophylline, a methylxanthine bronchodilator; dazoxiben, a thromboxane synthetase inhibitor; REV-6866, a 5-lipoxygenase inhibitor; LY53857, a 5-hydroxytryptamine receptor antagonist; and LY183001, a leukotriene D4/E4 antagonist, partially reversed Cdyn and reduced excised lung gas volume. Atropine, a cholinergic/muscarinic antagonist indomethacin, a cyclooxygenase inhibitor; pyrilamine, a histamine receptor antagonist; and SRI 63-072, a platelet activating factor antagonist, had little or no effect. For all animals, final Cdyn values were highly correlated with reduction of pulmonary gas trapping (r = -0.86, P less than .0001). We conclude that smooth muscle contraction is important in A23187-induced airway obstruction; 5-hydroxytryptamine, thromboxane A2 and lipoxygenase products may be involved in maintaining this response; and that this approach is useful for investigating reversal of ongoing airway constriction.

Topics: Airway Obstruction; Airway Resistance; Albuterol; Animals; Calcimycin; Dose-Response Relationship, Drug; Ergolines; Guinea Pigs; Leukotrienes; Lung Compliance; Male; Platelet Activating Factor; Serotonin; Thromboxane A2

Upon a specific allergic reaction mediators released from mast cells found free in the bronchial lumen or in the epithelial surface loosen the interepithelial cell tight-junctions allowing the entrance of more allergen to deeper mast cells. The primary and secondary mediators thereby generated induce further increased vascular permeability which leads to the entrance of plasma proteins and platelets. The other immediate responses induced by mediator release are smooth muscle constriction, mucus secretion and leukocyte chemoattraction. Vagal afferent and reflex efferent stimulation are induced by histamine and probably other mediators which might contribute both to the bronchospasm as well as mucous gland secretion. Subacute responses include increased cellular infiltrates, mucosal edema, desquamation, basement membrane thickening, goblet cell hyperplasia and mucus secretion. These responses may occur because of the continued release of primary and secondary mediators as well as effects caused by the mast cell granule matrix-derived factors. It can thus be seen that many of the pathologic features of asthma may be attributed to mast cell degranulation.

Topics: Airway Obstruction; Asthma; Bradykinin; Capillary Permeability; Histamine; Humans; Leukotriene E4; Mast Cells; Mucus; Muscle Contraction; Muscle, Smooth; Prostaglandins; SRS-A; Thromboxane A2