Abstract
A deep inspiration (DI) produces bronchodilation in healthy individuals. Conversely, in asthmatics, DIs are less effective in producing bronchodilation and can cause more rapid airway renarrowing and even bronchoconstriction in moderate to severe asthmatics. It is noteworthy that 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 thromboxane prostanoid (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 by using bovine bronchial segments. In brief, these intact bronchial segments (2 mm in diameter) were dissected, side branches were 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, a cyclooxygenase inhibitor, a result mimicked by pretreatment with the TP-selective receptor antagonist 4-(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid (ICI 192605) and the selective p42/p44 mitogen-activated protein kinase inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD 95089) and by airway epithelial denudation. 9,11-Dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U46619), a TP receptor agonist, elicited enhanced Rstretch responses in a dose-dependent manner. Pretreatment with 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809), a prostaglandin E (EP) receptor 1/prostaglandin D2 (DP)-selective receptor antagonist, and 9α,15R-dihydroxy-11.β-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta-5Z,13E-dien-1-oic acid (AL 8810), a prostaglandin F (FP)-selective receptor antagonist, had no effect, suggesting EP, DP, and FP receptor activation is not involved in amplifying airway smooth muscle 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.
Footnotes
This work was supported by the Canadian Institutes of Health Research [Grant MOP 15561] (to L.J.J.) and a National Science and Engineering Research Council studentship (to J.M.H.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.182246.
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ABBREVIATIONS:
- DI
- deep inspiration
- ACh
- acetylcholine
- AH 6809
- 6-isopropoxy-9-oxoxanthene-2-carboxylic acid
- AL 8810
- 9α,15R-dihydroxy-11.β-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta-5Z,13E-dien-1-oic acid
- ASM
- airway smooth muscle
- CCh
- carbachol (2-carbamoyloxyethyl-trimethyl-azanium)
- COX
- cyclooxygenase
- DP
- prostaglandin D2
- EIA
- enzyme immunoassay
- EP
- prostaglandin E
- FP
- prostaglandin F
- H&E
- hematoxylin and eosin
- ICI 192605
- 4-(Z)-6-(2-o-chlorophenyl-4-o-hydroxyphenyl-1,3-dioxan-cis-5-yl)hexenoic acid
- Indo
- indomethacin [2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid]
- MAPK
- mitogen-activated protein kinase
- NK
- neurokinin
- PD 95089
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
- PG
- prostaglandin
- RCCh
- CCh-induced bronchial tone
- Rstretch
- contraction evoked by an instantaneous stretch to cmH2O
- TP
- thromboxane prostanoid
- Tx
- thromboxane
- U46619
- 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid
- RU46619
- U46619-induced bronchial tone.
- Received March 30, 2011.
- Accepted July 14, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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