A deep inspiration (DI) produces bronchodilation in healthy individuals. Conversely, in asthmatics, DIs are less effective in producing bronchodilation, can cause more rapid airway re-narrowing and even bronchoconstriction in moderate to severe asthmatics. Interestingly, the manner by which a DI is able to cause bronchoconstriction via a stretch-activated contraction (Rstretch) is thought to correlate positively with airway inflammation. Asthmatic airway inflammation is associated with increased production of thromboxane A2 (TxA2) and subsequent TP-receptor activation, causing the heightened contractility of airway smooth muscle. In this study, we sought to investigate the effect of TxA2 on airway Rstretch using bovine bronchial segments. In brief, these intact bronchial segments (2mm dia.) were dissected, side branches ligated, and the tissues were mounted horizontally in an organ bath. Rstretch was elicited by varying the transmural pressure under isovolumic conditions. Using a pharmacological approach, we showed a reduced Rstretch response in tissues pretreated with indomethacin (Indo), a COX inhibitor; a result mimicked by pretreatment with the TP-selective receptor antagonist ICI 192605, the selective p42/p44 MAPK inhibitor PD 95089, and by airway epithelial denudation. U46619, a TP-receptor agonist elicited enhanced Rstretch responses in a dose-dependent manner. Pretreatment with AH 6809, an EP1/DP-selective receptor antagonist and AL 8810, an FP-selective receptor antagonist had no effect, suggesting EP, DP, and FP-receptor activation are not involved in amplifying ASM Rstretch. These data suggest a role for TP-receptor activation and epithelial release of TxA2 in amplifying airway Rstretch, thus providing novel insights into mechanisms regulating the DI-induced bronchoconstriction seen in asthmatics.
- Received March 30, 2011.
- Revision received July 11, 2011.
- Accepted July 14, 2011.
- The American Society for Pharmacology and Experimental Therapeutics