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Am J Physiol Lung Cell Mol Physiol (October 21, 2005). doi:10.1152/ajplung.00340.2005
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Submitted on August 3, 2005
Accepted on October 20, 2005

Thromboxane A2 Induces Airway Constriction Through An M3 Muscarinic Acetylcholine Receptor Dependent Mechanism

Coy Allen1, John Hartney1, Thomas Coffman2, Raymond B Penn3, Jurgen Wess4, and Beverly H Koller1*

1 Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Division of Nephrology, , Duke University Medical Center, Durham, NC, USA
3 Center For Human Genomics, Wake Forest University Health Science Center, Winston Salem, NC, USA
4 Laboratory of Bioorganic Chemistry, NIH-NIDDK, Bethesda, MD, USA

* To whom correspondence should be addressed. E-mail: Treawouns{at}aol.com.

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 pharmacologic and genetic strategies demonstrate that TP-dependent changes in lung resistance and airway smooth muscle tension require expression of the M3 mAChR subtype. These results raise the possibility that some of the beneficial actions of anticholinergic agents used in the treatment of asthma and COPD 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.




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