title: Revisiting the usefulness of thromboxane-A2 modulation in the treatment of bronchoconstriction in asthma.
abstract: Airway smooth muscle (ASM) is the effector cell in the bronchoconstrictory pathway. It is believed that the bronchoconstriction present in asthma is associated with changes in the airway milieu that affect ASM excitation-contraction coupling and Ca(2+)-handling. Asthmatics also react differently to ventilatory mechanical strain. Deep inspiration (DI), which produces bronchodilation in healthy individuals, is less effective in asthmatics, and even enhances bronchoconstriction in moderate to severely affected patients. Our laboratory has previously studied the mechanotransductory pathway of airway stretch-activated contractions (Rstretch) leading to DI-induced bronchoconstriction. We demonstrated the ability of agonists acting through thromboxane A2 (TxA2) receptors to amplify airway Rstretch responses. Despite the involvement of excitatory prostanoids in bronchoconstriction, clinical trials on treatments targeting TxA2-synthase inhibition and TP-receptor antagonism have produced mixed results. Studies in Western populations produced mostly negative results, whereas studies performed in Asian populations showed mostly positive outcomes. In this review, we discuss the role of TxA2-synthase inhibition and TP-receptor antagonism in the treatment of asthmatics. We present information regarding variations in study designs and the possible role of TP-receptor gene polymorphisms in previous study outcome discrepancies. Perhaps future studies should focus on asthmatic patients with DI-induced bronchoconstriction in particular, planting the seed for the individualized treatments for asthmatics.
authors.affiliation: Firestone Institute for Respiratory Health, Father Sean O'Sullivan Research Centre, and Department of Medicine, McMaster University, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, ON L8N 4A6, Canada.
authors.forename: Jeremy Mark
authors.initials: JM
authors.lastname: Hernandez
authors.forename: Luke Jeffrey
authors.initials: LJ
authors.lastname: Janssen
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008689:Methacrylates / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013928:Thromboxane A2 / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D016861:Cyclooxygenase Inhibitors; D008689:Methacrylates; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D011451:Prostaglandin-Endoperoxide Synthases; C034364:ozagrel
keywords: airway hyper-responsiveness; airway smooth muscle; antagoniste du récepteur du thromboxane-A2; calcium handling; couplage excitation–contraction; deep inspiration; excitation–contraction coupling; gestion du calcium; hyperréactivité bronchique; inhibiteur de la thromboxane-A2 synthase; inspiration profonde; muscle lisse respiratoire; prostanoids; prostanoïdes; thromboxane-A2 receptor antagonist; thromboxane-A2 synthase inhibitor