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Thromboxane prostanoid receptor activation amplifies airway stretch-activated contractions assessed in perfused intact bovine bronchial segments.
J Pharmacol Exp Ther. 2011 Oct; 339(1):248-56.JP

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 (R(stretch)) is thought to correlate positively with airway inflammation. Asthmatic airway inflammation is associated with increased production of thromboxane A(2) (TxA(2)) 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 TxA(2) on airway R(stretch) 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. R(stretch) was elicited by varying the transmural pressure under isovolumic conditions. Using a pharmacological approach, we showed a reduced R(stretch) 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 R(stretch) 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 R(stretch). These data suggest a role for TP receptor activation and epithelial release of TxA(2) in amplifying airway R(stretch), thus providing novel insights into mechanisms regulating the DI-induced bronchoconstriction seen in asthmatics.

Authors+Show Affiliations

Firestone Institute for Respiratory Health, Father Sean O'Sullivan Research Centre, and Department of Medicine, McMaster University, St Joseph's Hospital, Hamilton, Ontario, CanadaNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21768224

Citation

Hernandez, Jeremy Mark, and Luke Jeffrey Janssen. "Thromboxane Prostanoid Receptor Activation Amplifies Airway Stretch-activated Contractions Assessed in Perfused Intact Bovine Bronchial Segments." The Journal of Pharmacology and Experimental Therapeutics, vol. 339, no. 1, 2011, pp. 248-56.
Hernandez JM, Janssen LJ. Thromboxane prostanoid receptor activation amplifies airway stretch-activated contractions assessed in perfused intact bovine bronchial segments. J Pharmacol Exp Ther. 2011;339(1):248-56.
Hernandez, J. M., & Janssen, L. J. (2011). Thromboxane prostanoid receptor activation amplifies airway stretch-activated contractions assessed in perfused intact bovine bronchial segments. The Journal of Pharmacology and Experimental Therapeutics, 339(1), 248-56. https://doi.org/10.1124/jpet.111.182246
Hernandez JM, Janssen LJ. Thromboxane Prostanoid Receptor Activation Amplifies Airway Stretch-activated Contractions Assessed in Perfused Intact Bovine Bronchial Segments. J Pharmacol Exp Ther. 2011;339(1):248-56. PubMed PMID: 21768224.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Thromboxane prostanoid receptor activation amplifies airway stretch-activated contractions assessed in perfused intact bovine bronchial segments. AU - Hernandez,Jeremy Mark, AU - Janssen,Luke Jeffrey, Y1 - 2011/07/18/ PY - 2011/7/20/entrez PY - 2011/7/20/pubmed PY - 2011/12/13/medline SP - 248 EP - 56 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 339 IS - 1 N2 - 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 (R(stretch)) is thought to correlate positively with airway inflammation. Asthmatic airway inflammation is associated with increased production of thromboxane A(2) (TxA(2)) 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 TxA(2) on airway R(stretch) 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. R(stretch) was elicited by varying the transmural pressure under isovolumic conditions. Using a pharmacological approach, we showed a reduced R(stretch) 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 R(stretch) 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 R(stretch). These data suggest a role for TP receptor activation and epithelial release of TxA(2) in amplifying airway R(stretch), thus providing novel insights into mechanisms regulating the DI-induced bronchoconstriction seen in asthmatics. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/21768224/Thromboxane_prostanoid_receptor_activation_amplifies_airway_stretch_activated_contractions_assessed_in_perfused_intact_bovine_bronchial_segments_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21768224 DB - PRIME DP - Unbound Medicine ER -