title: Allergic inflammation induces a persistent mechanistic switch in thromboxane-mediated airway constriction in the mouse.
abstract: 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.
authors: Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7264, USA.
authors: Jaime M
authors: JM
authors: Cyphert
authors: Irving C
authors: IC
authors: Allen
authors: Rachel J
authors: RJ
authors: Church
authors: Anne M
authors: AM
authors: Latour
authors: John N
authors: JN
authors: Snouwaert
authors: Thomas M
authors: TM
authors: Coffman
authors: Beverly H
authors: BH
authors: Koller
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001249:Asthma / Q000473:pathology; D001980:Bronchi / Q000294:innervation* / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006967:Hypersensitivity / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D011014:Pneumonia / Q000503:physiopathology; D017482:Receptors, Thromboxane / Q000235:genetics / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000187:drug effects; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid