Thromboxane A2 induces airway constriction through an M3 muscarinic acetylcholine receptor-dependent mechanism.
Thromboxane A2 (TXA2) is a potent lipid mediator released by platelets and inflammatory cells and is capable of inducing vasoconstriction and bronchoconstriction. In the airways, it has been postulated that TXA2 causes airway constriction by direct activation of thromboxane prostanoid (TP) receptors on airway smooth muscle cells. Here we demonstrate that although TXA2 can mediate a dramatic increase in airway smooth muscle constriction and lung resistance, this response is largely dependent on vagal innervation of the airways and is highly sensitive to muscarinic acetylcholine receptor (mAChR) antagonists. Further analyses employing pharmacological and genetic strategies demonstrate that TP-dependent changes in lung resistance and airway smooth muscle tension require expression of the M2 mAChR subtype. These results raise the possibility that some of the beneficial actions of anticholinergic agents used in the treatment of asthma and chronic obstructive pulmonary disease result from limiting physiological changes mediated through the TP receptor. Furthermore, these findings demonstrate a unique pathway for TP regulation of homeostatic mechanisms in the airway and suggest a paradigm for the role of TXA2 in other organ systems.
Allen
Irving C
IC
Curriculum in Genetics and Molecular Biology, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Hartney
John M
JM
Coffman
Thomas M
TM
Penn
Raymond B
RB
Wess
Jürgen
J
Koller
Beverly H
BH
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000378:metabolism; D012137:Respiratory System; D013928:Thromboxane A2 / Q000494:pharmacology*; D014628:Vagotomy
D043587:Receptor, Muscarinic M3; D017482:Receptors, Thromboxane; D013928:Thromboxane A2