Allergic inflammation induces a persistent mechanistic switch in thromboxane-mediated airway constriction in the mouse

• Published in: American journal of physiology. Lung cellular and molecular physiology 2012-01, Vol.302 (1), p.L140-L151
• Main Authors: Cyphert, Jaime M, Allen, Irving C, Church, Rachel J, Latour, Anne M, Snouwaert, John N, Coffman, Thomas M, Koller, Beverly H
• Format: Article
• Language: English
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Airway Resistance - drug effects; Animals; Asthma - pathology; Bronchi - innervation; Bronchi - metabolism; Bronchoconstriction - drug effects; Bronchoconstriction - physiology; Cells, Cultured; Gene expression; Hypersensitivity - pathology; Lung diseases; Mice; Mice, Transgenic; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Neurons, Afferent - drug effects; Neurons, Afferent - physiology; Pathogenesis; Physiology; Pneumonia - physiopathology; Proteins; Receptors, Thromboxane - genetics; Receptors, Thromboxane - metabolism; Receptors, Thromboxane A2, Prostaglandin H2 - drug effects; Respiratory System - metabolism; Respiratory System - pathology; Rodents; Thromboxane A2 - analogs & derivatives; Thromboxane A2 - pharmacology; Vasoconstrictor Agents - pharmacology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00152.2011

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.