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Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs

Background Respiratory tract viral infections result in asthma exacerbations. Toll-like receptor (TLR) 7 is a receptor for viral single-stranded RNA and is expressed at high levels in the lungs. Objective Because TLR7 polymorphisms are associated with asthma, we examined the effects of TLR7 agonists... Full description

Journal Title: Journal of allergy and clinical immunology 2010, Vol.127 (2), p.462-469
Main Author: Kaufman, Elad H., BS
Other Authors: Fryer, Allison D., PhD , Jacoby, David B., MD
Format: Electronic Article Electronic Article
Language: English
Subjects:
RNA
Quelle: Alma/SFX Local Collection
Publisher: New York, NY: Mosby, Inc
ID: ISSN: 0091-6749
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3066064
title: Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs
format: Article
creator:
  • Kaufman, Elad H., BS
  • Fryer, Allison D., PhD
  • Jacoby, David B., MD
subjects:
  • adenosine
  • Adenosine - antagonists & inhibitors
  • Allergy and Immunology
  • Animals
  • asthma
  • Biological and medical sciences
  • Bronchoconstriction - drug effects
  • bronchodilator
  • Bronchodilator Agents - pharmacology
  • calcium-activated potassium channel
  • Chronic obstructive pulmonary disease, asthma
  • Dinoprostone - physiology
  • Female
  • guinea pig
  • Guinea Pigs
  • imiquimod
  • IRS661
  • Kinases
  • large-conductance
  • Large-Conductance Calcium-Activated Potassium Channels - physiology
  • large-conductance, calcium-activated potassium channel
  • Medical sciences
  • Muscular system
  • Nitric oxide
  • Nitric Oxide Synthase - physiology
  • Physiological aspects
  • Pneumology
  • Poly A - pharmacology
  • Poly U - pharmacology
  • prostaglandins
  • Respiratory agents
  • RNA
  • T-Lymphocytes, Helper-Inducer - immunology
  • Toll-like receptor 7
  • Toll-Like Receptor 7 - agonists
  • Toll-Like Receptor 7 - antagonists & inhibitors
  • Trachea - drug effects
  • Trachea - physiology
  • Viral infections
  • virus
  • Virus diseases
ispartof: Journal of allergy and clinical immunology, 2010, Vol.127 (2), p.462-469
description: Background Respiratory tract viral infections result in asthma exacerbations. Toll-like receptor (TLR) 7 is a receptor for viral single-stranded RNA and is expressed at high levels in the lungs. Objective Because TLR7 polymorphisms are associated with asthma, we examined the effects of TLR7 agonists in guinea pig airways. Methods We induced bronchoconstriction in guinea pigs in vivo by means of electrical stimulation of the vagus nerve or intravenous administration of acetylcholine and measured the effect of a TLR7 agonist administered intravenously. We induced contraction of airway smooth muscle in segments of isolated guinea pig tracheas in vitro and measured the effect of TLR7 agonists, antagonists, and pharmacologic inhibitors of associated signaling pathways administered directly to the bath. Results TLR7 agonists acutely inhibited bronchoconstriction in vivo and relaxed contraction of airway smooth muscle in vitro within minutes of administration. Airway relaxation induced by the TLR7 agonist R837 (imiquimod) was partially blocked with a TLR7 antagonist and was also blocked by inhibitors of large-conductance, calcium-activated potassium channels; prostaglandin synthesis; and nitric oxide generation. Another TLR7 agonist, 21-mer single-stranded phosphorothioated polyuridylic acid (PolyUs), mediated relaxation that was completely blocked by a TLR7 antagonist. Conclusions These data demonstrate a novel protective mechanism to limit bronchoconstriction and maintain airflow during respiratory tract viral infections. The fast time frame is inconsistent with canonical TLR7 signaling. R837 mediates bronchodilation by means of TLR7-dependent and TLR7-independent mechanisms, whereas PolyUs does so through only the TLR7-dependent mechanism. TLR7-independent mechanisms involve prostaglandins and large-conductance, calcium-activated potassium channels, whereas TLR7-dependent mechanisms involve nitric oxide. TLR7 is an attractive therapeutic target for its ability to reverse bronchoconstriction within minutes.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0091-6749
fulltext: fulltext
issn:
  • 0091-6749
  • 1097-6825
url: Link


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titleToll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs
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descriptionBackground Respiratory tract viral infections result in asthma exacerbations. Toll-like receptor (TLR) 7 is a receptor for viral single-stranded RNA and is expressed at high levels in the lungs. Objective Because TLR7 polymorphisms are associated with asthma, we examined the effects of TLR7 agonists in guinea pig airways. Methods We induced bronchoconstriction in guinea pigs in vivo by means of electrical stimulation of the vagus nerve or intravenous administration of acetylcholine and measured the effect of a TLR7 agonist administered intravenously. We induced contraction of airway smooth muscle in segments of isolated guinea pig tracheas in vitro and measured the effect of TLR7 agonists, antagonists, and pharmacologic inhibitors of associated signaling pathways administered directly to the bath. Results TLR7 agonists acutely inhibited bronchoconstriction in vivo and relaxed contraction of airway smooth muscle in vitro within minutes of administration. Airway relaxation induced by the TLR7 agonist R837 (imiquimod) was partially blocked with a TLR7 antagonist and was also blocked by inhibitors of large-conductance, calcium-activated potassium channels; prostaglandin synthesis; and nitric oxide generation. Another TLR7 agonist, 21-mer single-stranded phosphorothioated polyuridylic acid (PolyUs), mediated relaxation that was completely blocked by a TLR7 antagonist. Conclusions These data demonstrate a novel protective mechanism to limit bronchoconstriction and maintain airflow during respiratory tract viral infections. The fast time frame is inconsistent with canonical TLR7 signaling. R837 mediates bronchodilation by means of TLR7-dependent and TLR7-independent mechanisms, whereas PolyUs does so through only the TLR7-dependent mechanism. TLR7-independent mechanisms involve prostaglandins and large-conductance, calcium-activated potassium channels, whereas TLR7-dependent mechanisms involve nitric oxide. TLR7 is an attractive therapeutic target for its ability to reverse bronchoconstriction within minutes.
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subjectadenosine ; Adenosine - antagonists & inhibitors ; Allergy and Immunology ; Animals ; asthma ; Biological and medical sciences ; Bronchoconstriction - drug effects ; bronchodilator ; Bronchodilator Agents - pharmacology ; calcium-activated potassium channel ; Chronic obstructive pulmonary disease, asthma ; Dinoprostone - physiology ; Female ; guinea pig ; Guinea Pigs ; imiquimod ; IRS661 ; Kinases ; large-conductance ; Large-Conductance Calcium-Activated Potassium Channels - physiology ; large-conductance, calcium-activated potassium channel ; Medical sciences ; Muscular system ; Nitric oxide ; Nitric Oxide Synthase - physiology ; Physiological aspects ; Pneumology ; Poly A - pharmacology ; Poly U - pharmacology ; prostaglandins ; Respiratory agents ; RNA ; T-Lymphocytes, Helper-Inducer - immunology ; Toll-like receptor 7 ; Toll-Like Receptor 7 - agonists ; Toll-Like Receptor 7 - antagonists & inhibitors ; Trachea - drug effects ; Trachea - physiology ; Viral infections ; virus ; Virus diseases
ispartofJournal of allergy and clinical immunology, 2010, Vol.127 (2), p.462-469
rights
0American Academy of Allergy, Asthma & Immunology
12010 American Academy of Allergy, Asthma & Immunology
22015 INIST-CNRS
3Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
4COPYRIGHT 2011 Elsevier B.V.
5Copyright Elsevier Limited Feb 2011
62010 American Academy of Allergy, Asthma & Immunology 2010
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descriptionBackground Respiratory tract viral infections result in asthma exacerbations. Toll-like receptor (TLR) 7 is a receptor for viral single-stranded RNA and is expressed at high levels in the lungs. Objective Because TLR7 polymorphisms are associated with asthma, we examined the effects of TLR7 agonists in guinea pig airways. Methods We induced bronchoconstriction in guinea pigs in vivo by means of electrical stimulation of the vagus nerve or intravenous administration of acetylcholine and measured the effect of a TLR7 agonist administered intravenously. We induced contraction of airway smooth muscle in segments of isolated guinea pig tracheas in vitro and measured the effect of TLR7 agonists, antagonists, and pharmacologic inhibitors of associated signaling pathways administered directly to the bath. Results TLR7 agonists acutely inhibited bronchoconstriction in vivo and relaxed contraction of airway smooth muscle in vitro within minutes of administration. Airway relaxation induced by the TLR7 agonist R837 (imiquimod) was partially blocked with a TLR7 antagonist and was also blocked by inhibitors of large-conductance, calcium-activated potassium channels; prostaglandin synthesis; and nitric oxide generation. Another TLR7 agonist, 21-mer single-stranded phosphorothioated polyuridylic acid (PolyUs), mediated relaxation that was completely blocked by a TLR7 antagonist. Conclusions These data demonstrate a novel protective mechanism to limit bronchoconstriction and maintain airflow during respiratory tract viral infections. The fast time frame is inconsistent with canonical TLR7 signaling. R837 mediates bronchodilation by means of TLR7-dependent and TLR7-independent mechanisms, whereas PolyUs does so through only the TLR7-dependent mechanism. TLR7-independent mechanisms involve prostaglandins and large-conductance, calcium-activated potassium channels, whereas TLR7-dependent mechanisms involve nitric oxide. TLR7 is an attractive therapeutic target for its ability to reverse bronchoconstriction within minutes.
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abstractBackground Respiratory tract viral infections result in asthma exacerbations. Toll-like receptor (TLR) 7 is a receptor for viral single-stranded RNA and is expressed at high levels in the lungs. Objective Because TLR7 polymorphisms are associated with asthma, we examined the effects of TLR7 agonists in guinea pig airways. Methods We induced bronchoconstriction in guinea pigs in vivo by means of electrical stimulation of the vagus nerve or intravenous administration of acetylcholine and measured the effect of a TLR7 agonist administered intravenously. We induced contraction of airway smooth muscle in segments of isolated guinea pig tracheas in vitro and measured the effect of TLR7 agonists, antagonists, and pharmacologic inhibitors of associated signaling pathways administered directly to the bath. Results TLR7 agonists acutely inhibited bronchoconstriction in vivo and relaxed contraction of airway smooth muscle in vitro within minutes of administration. Airway relaxation induced by the TLR7 agonist R837 (imiquimod) was partially blocked with a TLR7 antagonist and was also blocked by inhibitors of large-conductance, calcium-activated potassium channels; prostaglandin synthesis; and nitric oxide generation. Another TLR7 agonist, 21-mer single-stranded phosphorothioated polyuridylic acid (PolyUs), mediated relaxation that was completely blocked by a TLR7 antagonist. Conclusions These data demonstrate a novel protective mechanism to limit bronchoconstriction and maintain airflow during respiratory tract viral infections. The fast time frame is inconsistent with canonical TLR7 signaling. R837 mediates bronchodilation by means of TLR7-dependent and TLR7-independent mechanisms, whereas PolyUs does so through only the TLR7-dependent mechanism. TLR7-independent mechanisms involve prostaglandins and large-conductance, calcium-activated potassium channels, whereas TLR7-dependent mechanisms involve nitric oxide. TLR7 is an attractive therapeutic target for its ability to reverse bronchoconstriction within minutes.
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