Thromboxane A₂induces airway constriction through an M₃muscarinic acetylcholine receptor-dependent mechanism

Abstract

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.

Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease

“…To begin to address this possibility, we examined the change in airway responsiveness of the 129/SvEv GPRA Ϫ/Ϫ mice and their genetic controls to thromboxane. Previous studies have demonstrated that the increase in airway and tissue resistance in the mouse in response to this agent is dependent on an intact cholinergic pathway (2). As seen in Fig.…”

“…The difference appears to be confined to the central airways, as no significant difference was observed in the G and H parameters, which are sensitive to changes in the distal lung. Previous studies have demonstrated that U-46619 facilitates airway smooth muscle constriction through an M 3 muscarinic acetylcholine receptor-dependent mechanism (2). It has been suggested that this mechanism likely involves afferent and efferent neural signaling (1,2,15).…”

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

“…Also, TxB 2 was abundant in the conditioned media from both Mf types. TxA 2 is often described as proinflammatory (e.g., in muscarinic acetylcholine receptor-mediated airway constriction) (38). However, TxA 2 -TP signaling also modulated immunity to foreign antigens by negatively regulating dendritic cell-T cell interactions (39).…”

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

“…Thus AHR following the early asthmatic reaction is reversed by anticholinergics [141], and the bronchoconstrictor response of inhaled inflammatory mediators (e.g. histamine and thromboxane A 2 ) is, to a large extent, mediated by cholinergic pathways [141,159].…”