thromboxane-a2 and Hypersensitivity

Topics: Anti-Allergic Agents; Cromolyn Sodium; Cytokines; Dosage Forms; Drug Design; Glucocorticoids; Histamine Antagonists; Humans; Hypersensitivity; Leukotriene Antagonists; Mast Cells; Practice Guidelines as Topic; Th1 Cells; Th2 Cells; Thromboxane A2

The purpose of this review is to summarize the role of prostaglandins (PGs) in allergic inflammation and to know the value of PGs, as a target molecule for an anti-allergic drug. PGD(2) is the major PG produced by the cyclooxygenase pathway in mast cells. Our and others findings indicate that PGD(2) is one of the potent allergic inflammatory mediators and must be a target molecule of anti-allergic agent. From our data, one of PGD(2) receptor antagonists show clear inhibition of airway hypersensitivity caused by allergic reaction. Concerning the role of PGE(2) in allergic inflammation, conflicting results have been reported. Many experimental data suggest an individual role of each PGE(2) receptor, EP(1), EP(2), EP(3) and EP(4) in allergic reaction. Our results indicate the protective action of PGE(2) on allergic reaction via EP(3). In addition, one of EP(3) agonists clearly inhibits the allergic airway inflammation. These findings indicate the value of EP(3) agonists as an anti-allergic agent. In addition, some investigators including us reported that PGI(2) plays an important role for the protection of the onset of allergic reaction. However, the efficacy of PGI(2) analogue as an anti-allergic agent is not yet fully investigated. Finally, the role of thromboxane A(2) (TxA(2)) in allergic reaction is discussed. Our experimental results suggest a different participation of TxA(2) in allergic reaction of airway and skin. In this review, the role of PGs in allergic inflammation is summarized and the value of PGs as a target molecule for developing a new anti-allergic agent will be discussed.

Topics: Animals; Anti-Allergic Agents; Bronchial Provocation Tests; Disease Models, Animal; Humans; Hypersensitivity; Mice; Prostaglandins; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype; Thromboxane A2

Research over the past decade has provided information concerning the onset and treatment of allergic diseases, including bronchial asthma, allergic rhinitis and atopic dermatitis. Recent studies also indicated that allergic inflammation is the basic pathophysiology of allergic diseases and is closely associated with their progression and exacerbation. Our understanding of the mechanism of allergic inflammation with regard to therapeutic agents has improved as a result of immunological and molecular biological studies. While much effort has been paid to developing a new anti-allergic drug, allergic disease has yet to be completely conquered. More extensive research will allow the development of new therapeutics to combat allergic diseases. This article provides an overview of recent advances in the development of anti-allergic drugs.

Topics: Anti-Allergic Agents; Chemistry, Pharmaceutical; Histamine H1 Antagonists, Non-Sedating; Humans; Hypersensitivity; Leukotriene Antagonists; Thromboxane A2

Immunologic or calcium-dependent activation of proteolytically dispersed human lung cells containing 5% mast cells causes the release of large amounts of PGD2 and TxB2. In cell purification experiments, only those fractions containing mast cells had the capacity to generate PGD2 and release histamine with IgE-dependent activation. The cells of origin of T X B2 are likely to be cells of the monocyte-macrophage series, although additional eicosanoid release may occur from immunologically activated lymphocytes and eosinophils. In men who have asthma, inhalation of low concentrations of PGD2 results in bronchoconstriction, whereas higher concentrations of PGD2 are needed to produce bronchoconstriction in normal subjects. Subjects with asthma exhibited 3.5-fold greater responsiveness to inhaled PGD2 than to PGF2 alpha. These observations demonstrate that PGD2 is the most potent bronchoconstrictor prostanoid tested in man. In both normal subjects and subjects with asthma, a single inhalation of PGF2 alpha resulted in a doubling in plasma levels of 13,14-dihydro-15-keto-PGF2 alpha. Plasma levels of this metabolite did not change after PGD2 inhalation. These results indicate that the 11-keto reduction of PGD2 to PGF2 alpha with subsequent inactivation is not important in the initial metabolism of PGD2.

Topics: Airway Resistance; Animals; Antibodies, Anti-Idiotypic; Asthma; Calcimycin; Cells, Cultured; Epoprostenol; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Lung; Prostaglandins; Thromboxane A2

A problem of leukotrienes--metabolites of arachidonic acid is reviewed in immunological aspects. Their nomenclature is given; basic pathways of biosynthesis, transformation and mode of leukotriens participation in hypersensitivity and inflammatory reactions are considered. The possibility of application of leukotrienes antagonists and inhibitors of their formation for allergic diseases treatment is discussed.

Topics: Animals; Antigens; Arachidonic Acids; Drug Synergism; Guinea Pigs; Humans; Hypersensitivity; Inflammation; Leukotriene B4; Neurotransmitter Agents; Rabbits; Receptors, Immunologic; SRS-A; Structure-Activity Relationship; Terminology as Topic; Thromboxane A2

Actions of thromboxane (TXA(2)) to alter airway resistance were first identified over 25 years ago. However, the mechanism underlying this physiological response has remained largely undefined. Here we address this question using a novel panel of mice in which expression of the thromboxane receptor (TP) has been genetically manipulated. We show that the response of the airways to TXA(2) is complex: it depends on expression of other G protein-coupled receptors but also on the physiological context of the signal. In the healthy airway, TXA(2)-mediated airway constriction depends on expression of TP receptors by smooth muscle cells. In contrast, in the inflamed lung, the direct actions of TXA(2) on smooth muscle cell TP receptors no longer contribute to bronchoconstriction. Instead, in allergic lung disease, TXA(2)-mediated airway constriction depends on neuronal TP receptors. Furthermore, this mechanistic switch persists long after resolution of pulmonary inflammation. Our findings demonstrate the powerful ability of lung inflammation to modify pathways leading to airway constriction, resulting in persistent changes in mechanisms of airway reactivity to key bronchoconstrictors. Such alterations are likely to shape the pathogenesis of asthmatic lung disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Airway Resistance; Animals; Asthma; Bronchi; Bronchoconstriction; Cells, Cultured; Hypersensitivity; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Neurons, Afferent; Pneumonia; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Respiratory System; Thromboxane A2; Vasoconstrictor Agents

Low frequency (4-12 cpm) spontaneous fluctuations of the cerebrovascular tone (vasomotion) and oscillations of the cerebral blood flow (CBF) have been reported in diseases associated with endothelial dysfunction. Since endothelium-derived nitric oxide (NO) suppresses constitutively the release and vascular effects of thromboxane A(2) (TXA(2)), NO-deficiency is often associated with activation of thromboxane receptors (TP). In the present study we hypothesized that in the absence of NO, overactivation of the TP-receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations.. Effects of pharmacological modulation of TP-receptor activation and its downstream signaling pathway have been investigated on CBF oscillations (measured by laser-Doppler flowmetry in anesthetized rats) and vasomotion (measured by isometric tension recording in isolated rat middle cerebral arteries, MCAs) both under physiological conditions and after acute inhibition of NO synthesis. Administration of the TP-receptor agonist U-46619 (1 µg/kg i.v.) to control animals failed to induce any changes of the systemic or cerebral circulatory parameters. Inhibition of the NO synthesis by nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.v.) resulted in increased mean arterial blood pressure and a decreased CBF accompanied by appearance of CBF-oscillations with a dominant frequency of 148±2 mHz. U-46619 significantly augmented the CBF-oscillations induced by L-NAME while inhibition of endogenous TXA(2) synthesis by ozagrel (10 mg/kg i.v.) attenuated it. In isolated MCAs U-46619 in a concentration of 100 nM, which induced weak and stable contraction under physiological conditions, evoked sustained vasomotion in the absence of NO, which effect could be completely reversed by inhibition of Rho-kinase by 10 µM Y-27632.. These results suggest that hypersensitivity of the TP-receptor-Rho-kinase signaling pathway contributes to the development of low frequency cerebral vasomotion which may propagate to vasospasm in pathophysiological states associated with NO-deficiency.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Brain; Cerebrovascular Circulation; Enzyme Inhibitors; Hypersensitivity; Laser-Doppler Flowmetry; Male; Middle Cerebral Artery; Motion; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Receptors, Thromboxane; rho-Associated Kinases; Signal Transduction; Thromboxane A2

Our in vivo assay system developed to search for allergy-preventive substances, assesses the blood flow decrease in tail vein microcirculation of mice subjected to sensitization with hen-egg white lysozyme (HEL). The blood flow decrease appears to be regulated by various factors such as nitric oxide (NO), thromboxane (TX) A(2), prostacyclin (PGI(2)) and endothelin (ET)-1 together with cyclooxygenase (COX)-1, COX-2, inducible nitric oxide synthase (iNOS), and constitutive nitric oxide synthase (cNOS). In this study, we examined in detail the roles of iNOS in this assay system using an iNOS knockout (KO) mouse. We found that the blood flow decrease in the HEL-sensitized iNOS KO mice was slightly weaker than that in their wild type (WT) mice. This blood flow decrease was not affected by a selective COX-1 inhibitor, a selective COX-2 inhibitor and a PGI(2) agonist unlike the case of the WT mice. However, it was inhibited by a nonselective NOS inhibitor, a specific TXA(2) synthase inhibitor and a specific ET-1 receptor blocker as in the case of the WT mice. The present results indicate that the blood flow decrease occurs via two pathways; one is an iNOS-independent response involving TXA(2) and ET-1, and the other is an iNOS-dependent response involving COX-1, COX-2 and PGI(2). cNOS appears to play some roles in the blood flow decrease and iNOS acts as an exacerbation factor. Our method using HEL-sensitized should be useful for searching for agents that can prevent allergy via new mechanisms.

Topics: Animals; Epoprostenol; Female; Hypersensitivity; Methacrylates; Mice; Mice, Inbred C57BL; Muramidase; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type II; Nitrobenzenes; Peptides, Cyclic; Regional Blood Flow; Sulfonamides; Thromboxane A2; Veins

We examined whether cysteinyl leukotrienes (CysLTs) and thromboxane (TX) A2 are synergistically involved in a cedar pollen-induced allergic late phase nasal blockage in guinea pigs. Sensitized animals were repeatedly challenged by pollen inhalation once every week. Combined treatment with pranlukast (a CysLT antagonist) and seratrodast (a TXA2 antagonist) inhibited late phase nasal blockage, but the magnitude of inhibition (approximately 50%) was equal to those of the respective single treatments, suggesting that CysLTs produced late after challenge induces TXA2 production in the nasal tissue, as in the case of the lung of this species. However, pranlukast did not affect TXB2 increase in the nasal tissue. In contrast, combined intranasal instillation of LTD4 and U-46619 (a TXA2 mimetic) produced much greater nasal blockage than single administration of each agonist in sensitized animals. Therefore, allergic late phase nasal blockage should be induced by synergistic activity of CysLTs and TXA2 at the effector organ.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzoquinones; Chromones; Guinea Pigs; Heptanoic Acids; Hypersensitivity; Leukotriene D4; Leukotrienes; Male; Nasal Cavity; Thromboxane A2

Intravenous administration of some liposomal drugs can trigger immediate hypersensitivity reactions that include symptoms of cardiopulmonary distress. The mechanism underlying the cardiovascular changes has not been clarified.. Anesthetized pigs (n=18) were injected intravenously with 5-mg boluses of large multilamellar liposomes, and the ensuing hemodynamic, hematologic, and laboratory changes were recorded. The significant (P<0.01) alterations included 79+/-9% (mean+/-SEM) rise in pulmonary arterial pressure, 30+/-7% decline in cardiac output, 11+/-2% increase in heart rate, 236+/-54% increase in pulmonary vascular resistance, 71+/-27% increase in systemic vascular resistance, and up to a 100-fold increase in plasma thromboxane B2. These changes peaked between 1 and 5 minutes after injection, subsided within 10 to 20 minutes, were lipid dose-dependent (ED50=4. 5+/-1.4 mg), and were quantitatively reproducible in the same animal several times over 7 hours. The liposome-induced rises of pulmonary arterial pressure showed close quantitative and temporal correlation with elevations of plasma thromboxane B2 and were inhibited by an anti-C5a monoclonal antibody (GS1), by sCR1, or by indomethacin. Liposomes caused C5a production in pig serum in vitro through classic pathway activation and bound IgG and IgM natural antibodies. Zymosan- and hemoglobin-containing liposomes and empty liposomes caused essentially identical pulmonary changes.. The intense, nontachyphylactic, highly reproducible, complement-mediated pulmonary hypertensive effect of minute amounts of intravenous liposomes in pigs represents a unique, unexplored phenomenon in circulation physiology. The model provides highly sensitive detection and study of cardiopulmonary side effects of liposomal drugs and many other pharmaceutical products due to "complement activation-related pseudoallergy" (CARPA).

Topics: Animals; Complement Activation; Complement C5a; Complement System Proteins; Female; Hemodynamics; Hemoglobins; Humans; Hypersensitivity; Indomethacin; Infant, Newborn; Liposomes; Pulmonary Circulation; Receptors, Complement 3d; Respiratory Distress Syndrome, Newborn; Swine; 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

The effect of a novel thromboxane A2 receptor antagonist, BAY-u-3405, on experimental allergic airway and skin reactions was studied in vivo. At doses of 3-30 mg/kg BAY-u-3405 clearly inhibited the U-46619-induced increase in respiratory resistance (Rrs) in guinea pigs. BAY-u-3405 at doses of 3 and 30 mg/kg inhibited the aerosolized antigen-induced biphasic increase in respiratory resistance in guinea pigs. Moreover, BAY-u-3405 inhibited repeated aeroantigen-induced airway hyperactivity and airway inflammation in mice. In IgE antibody-mediated biphasic skin reactions in mice, both immediate and late-phase reactions were inhibited by 10 mg/kg of BAY-u-3405. These results demonstrate the efficacy of BAY-u-3405 on the antigen-induced late-phase reactions in the airway and skin in guinea pigs and mice, and antigen-induced airway hyperactivity in mice.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bronchial Hyperreactivity; Carbazoles; Dermatitis; Guinea Pigs; Hypersensitivity; Immunoglobulin E; Male; Mice; Mice, Inbred BALB C; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

Although it is well recognized that beta-blockers can induce bronchoconstriction only in patients with asthma, mechanisms of the bronchoconstriction are not well known. We hypothesize that bronchoconstriction induced by beta-blockers may result from inflammatory mediators released by allergic reactions. In this study, we developed a guinea pig model for propranolol-induced bronchoconstriction (PIB) after antigen inhalation and investigated the effect of specific thromboxane (TXA2) receptor antagonists, S-1452 and ONO NT-126, on PIB in passively sensitized and artificially ventilated guinea pigs to determine whether TXA2 is involved in PIB. Propranolol caused bronchoconstriction with 10 mg/ml of propranolol was inhaled 20 min after antigen challenge. On the other hand, propranolol did not produce bronchoconstriction after antigen provocation in nonsensitized guinea pigs or after saline provocation in sensitized animals. Pretreatment of the animals with S-1452 in doses of 0.01 and 0.1 mg/kg and ONO NT-126 in doses of 1.0 and 10 micrograms/kg injected intravenously 15 min after antigen challenge as well as before antigen challenge reduced PIB in a dose-dependent manner. Bronchoconstriction caused by methacholine did not induce PIB. These results suggest that TXA2 has an important role in the pathophysiology of the PIB that develops after the allergic bronchoconstriction.

Topics: Administration, Inhalation; Analysis of Variance; Animals; Asthma; Bridged Bicyclo Compounds; Bronchial Provocation Tests; Constriction, Pathologic; Disease Models, Animal; Dose-Response Relationship, Drug; Fatty Acids, Monounsaturated; Guinea Pigs; Hypersensitivity; Inflammation; Injections, Intravenous; Male; Methacholine Chloride; Premedication; Propranolol; Receptors, Prostaglandin; Thromboxane A2; Time Factors

We studied changes in airway responsiveness to acetylcholine (ACh) after antigen inhalation in Ascaris suum (A. suum)-allergic dogs. Airway responsiveness was determined by obtaining a dose-response curve of lung resistance plotted against increasing concentrations of ACh aerosol before and after inhalation of A. suum antigen. To determine the role of thromboxane A2 (TXA2) in the airway response, we tested the effect of a TXA2 receptor antagonist, AA-2414, in A. suum-allergic dogs. The procedure was repeated in each dog at an interval of 2 weeks to evaluate the effect of AA-2414 in a crossover manner. The dogs showing an airway response to antigen showed an increase in airway responsiveness to ACh 2, 4 and 6 h after antigen inhalation. The increase in airway responsiveness was significantly inhibited by administration of AA-2414 (5 mg/kg, i.v.) before antigen inhalation. These results suggest that TXA2 may be involved in antigen-induced airway hyperresponsiveness (AHR) in dogs.

Topics: Acetylcholine; Administration, Inhalation; Animals; Antigens, Helminth; Ascaris suum; Benzoquinones; Bronchoconstriction; Dogs; Female; Heptanoic Acids; Hypersensitivity; Male; Quinones; Receptors, Thromboxane; Respiratory System; Thromboxane A2

A new antiallergic agent with thromboxane A2 antagonistic activity, KW4099, was synthesized by a simple method. Its optical resolution was accomplished with the use of (+)- or (-)-2,2'-(1,1'-binaphthyl)phosphoric acid as a resolving agent.

Topics: Dibenzoxepins; Hypersensitivity; Piperidines; Stereoisomerism; Thromboxane A2

Calves given 2 subcutaneous inoculations (4 ml, 4.5 weeks apart) of an inactivated bluetongue virus serotype 17 (BTV-17), aluminum hydroxide adjuvant, and cimetidine (600 mg) or levamisole (819 mg, 6 ml) combination were challenge exposed with virulent BTV-17 (2.5 x 10(5) embryo lethal dose) 9 weeks after the 1st inoculation and were monitored for 35 days. Plasma prostaglandins (PG) and thromboxane (Tx) B2 were measured by radioimmunoassay. Histamine was assayed spectrofluorometrically. During the inoculation period (9 weeks from the 1st inoculation to challenge exposure) PGE and histamine increased from base-line concentrations of 34 +/- 3 pg/ml and 1.2 +/- 0.1 ng/ml to 83 +/- 8 pg/ml and 2.0 +/- 0.1 ng/ml, respectively, whereas PGF2 alpha decreased from base-line values of 356 +/- 41 pg/ml to 226 +/- 16 pg/ml. Significant (P less than or equal to 0.05) changes from base-line TxB2 values (110 +/- 7 pg/ml) were not observed during the inoculation period. After challenge exposure, maximum increases were observed in TxB2 (157 +/- 10 pg/ml), PGF2 alpha (713 +/- 93 pg/ml), PGE (140 +/- 30 pg/ml), and histamine (3.6 +/- 0.2 ng/ml) concentrations at 4, 7, 7, and 14 days after challenge exposure, respectively. Concentrations of PGF2 alpha and TxB2 decreased from base-line values to 211 +/- 42 pg/ml and 75 +/- 11 pg/ml, respectively, 21 days after challenge exposure and then returned to base-line values. Significant changes were not observed in plasma concentrations of 6-keto-PGF1 alpha. Results indicate that PG, TxA2, and histamine may be involved in the hypersensitivity reaction to BTV in cattle.

Topics: Animals; Bluetongue; Bluetongue virus; Cattle; Cattle Diseases; Cimetidine; Histamine; Hypersensitivity; Levamisole; Prostaglandins; Sheep; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: Animals; Atropine; Guinea Pigs; Histamine; Hypersensitivity; Isoproterenol; Lung; Male; Ovalbumin; Phenylephrine; Practolol; Prostaglandins; Sotalol; SRS-A; Thromboxane A2; Thromboxanes