15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Hypersensitivity

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

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

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

In asthmatics, both the continuous release of mast cell-derived inflammatory mediators and damage of the airway epithelium may be related to the degree of bronchial responsiveness. We therefore evaluated the effect of inflammatory mediators and mast cell activation on the cholinergic responsiveness of strips of human bronchioles with and without epithelium. Cumulative concentration-response curves to methacholine were generated from strips with or without epithelium before, during and after incubation with threshold doses of either methacholine (3 x 10(-7) M, controls), histamine (3 x 10(-7) M), the thromboxane A2 analogue, U46619 (10(-9) M), prostaglandin (PG) D2 (3 x 10(-7) M), PGF2 alpha (3 x 10(-7) M), leukotriene (LT) C4 (10(-9) M), or anti-human immunoglobulin E (24.4 +/- 4.0 micrograms.ml-1). Strips without epithelium were 1.6 times more sensitive to methacholine than strips with epithelium (-log EC50:5.76 +/- 0.04 vs. 5.97 +/- 0.04, P less than 0.0001). The average contraction in response to identical doses of anti-IgE in strips without epithelium was 3 times greater than the contraction in strips with epithelium (P less than 0.05). Threshold concentrations of histamine, U44619 and PGD2 caused a similar non-parallel leftward shift of the concentration-response curve of strips with or without epithelium to methacholine (P less than 0.05). Together, epithelial denudation and low levels of mediators caused a 4.0- to 9.1-fold increase in sensitivity based on the -log EC10 and a 1.8- to 3.0-fold increase in sensitivity based on the -log EC50.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aged; Aged, 80 and over; Antibodies, Anti-Idiotypic; Dinoprost; Epithelium; Histamine; Humans; Hypersensitivity; Immunoglobulin E; In Vitro Techniques; Inflammation; Kinetics; Lung; Male; Mast Cells; Methacholine Chloride; Middle Aged; Muscle Contraction; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; SRS-A