The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation.
Identifieur interne : 000D53 ( Main/Exploration ); précédent : 000D52; suivant : 000D54The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation.
Auteurs : Olivia J. Larsson [Suède] ; Martijn L. Manson [Suède] ; Magnus Starkhammar ; Barbara Fuchs [Suède] ; Mikael Adner [Suède] ; Susanna Kumlien Georén ; Lars-Olaf Cardell [Suède]Source :
- American journal of physiology. Lung cellular and molecular physiology [ 1522-1504 ] ; 2016.
Descripteurs français
- KwdFr :
- Aminoquinoléines (pharmacologie), Animaux, Asthme (traitement médicamenteux), Bronchioles (), Bronchioles (physiologie), Bronchodilatateurs (pharmacologie), Cellules cultivées, Cochons d'Inde, Humains, Myocytes du muscle lisse (), Myocytes du muscle lisse (physiologie), Mâle, Récepteur de type Toll-7 (agonistes), Signalisation du calcium, Évaluation préclinique de médicament.
- MESH :
- agonistes : Récepteur de type Toll-7.
- pharmacologie : Aminoquinoléines, Bronchodilatateurs.
- physiologie : Bronchioles, Myocytes du muscle lisse.
- traitement médicamenteux : Asthme.
- Animaux, Bronchioles, Cellules cultivées, Cochons d'Inde, Humains, Myocytes du muscle lisse, Mâle, Signalisation du calcium, Évaluation préclinique de médicament.
English descriptors
- KwdEn :
- Aminoquinolines (pharmacology), Animals, Asthma (drug therapy), Bronchioles (drug effects), Bronchioles (physiology), Bronchodilator Agents (pharmacology), Calcium Signaling, Cells, Cultured, Drug Evaluation, Preclinical, Guinea Pigs, Humans, Imiquimod, Male, Myocytes, Smooth Muscle (drug effects), Myocytes, Smooth Muscle (physiology), Toll-Like Receptor 7 (agonists).
- MESH :
- chemical , agonists : Toll-Like Receptor 7.
- chemical , pharmacology : Aminoquinolines, Bronchodilator Agents.
- drug effects : Bronchioles, Myocytes, Smooth Muscle.
- drug therapy : Asthma.
- physiology : Bronchioles, Myocytes, Smooth Muscle.
- Animals, Calcium Signaling, Cells, Cultured, Drug Evaluation, Preclinical, Guinea Pigs, Humans, Imiquimod, Male.
Abstract
Toll-like receptor (TLR) 7 agonists are known to reduce allergic airway inflammation. Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo. Pharmacological inhibitors were used to dissect conventional pathways of bronchodilation; tetrodotoxin was used or bilateral vagotomy was performed to assess neuronal involvement. Human ASM cells (HASMCs) were employed to determine the effect of TLR7 agonists on intracellular Ca(2+) ([Ca(2+)]i) mobilization. The well-established TLR7 agonist imiquimod rapidly relaxed precontracted airways in vitro and in vivo. This relaxation was demonstrated to be independent of nitric oxide, carbon monoxide, and cAMP signaling, as well as neuronal activity. A limited role for prostanoids could be detected. Imiquimod induced [Ca(2+)]i release from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca(2+)]i The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca(2+)]i This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca(2+)]i The effect is paralleled by other bronchorelaxant compounds, like chloroquine, which, like imiquimod, but unlike CL264, contains the chemical structure quinoline. Compounds with quinoline moieties may be of interest in the development of multifunctional drugs to treat pulmonary disease.
DOI: 10.1152/ajplung.00288.2015
PubMed: 27084847
Affiliations:
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Larsson</name><affiliation wicri:level="3"><nlm:affiliation>Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Manson, Martijn L" sort="Manson, Martijn L" uniqKey="Manson M" first="Martijn L" last="Manson">Martijn L. Manson</name><affiliation wicri:level="3"><nlm:affiliation>Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and Institute for Environmental Medicine, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Starkhammar, Magnus" sort="Starkhammar, Magnus" uniqKey="Starkhammar M" first="Magnus" last="Starkhammar">Magnus Starkhammar</name><affiliation><nlm:affiliation>Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and.</nlm:affiliation><wicri:noCountry code="subField">Sweden; and</wicri:noCountry></affiliation></author><author><name sortKey="Fuchs, Barbara" sort="Fuchs, Barbara" uniqKey="Fuchs B" first="Barbara" last="Fuchs">Barbara Fuchs</name><affiliation wicri:level="3"><nlm:affiliation>Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden;</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Adner, Mikael" sort="Adner, Mikael" uniqKey="Adner M" first="Mikael" last="Adner">Mikael Adner</name><affiliation wicri:level="3"><nlm:affiliation>Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and Institute for Environmental Medicine, Karolinska Institutet, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author><author><name sortKey="Kumlien Georen, Susanna" sort="Kumlien Georen, Susanna" uniqKey="Kumlien Georen S" first="Susanna" last="Kumlien Georén">Susanna Kumlien Georén</name><affiliation><nlm:affiliation>Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and.</nlm:affiliation><wicri:noCountry code="subField">Sweden; and</wicri:noCountry></affiliation></author><author><name sortKey="Cardell, Lars Olaf" sort="Cardell, Lars Olaf" uniqKey="Cardell L" first="Lars-Olaf" last="Cardell">Lars-Olaf Cardell</name><affiliation wicri:level="3"><nlm:affiliation>Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Department of ENT Disease, Karolinska University Hospital, Stockholm, Sweden; lars-olaf.cardell@ki.se.</nlm:affiliation><country wicri:rule="url">Suède</country><wicri:regionArea>Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Department of ENT Disease, Karolinska University Hospital, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author></analytic><series><title level="j">American journal of physiology. Lung cellular and molecular physiology</title><idno type="eISSN">1522-1504</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aminoquinolines (pharmacology)</term><term>Animals</term><term>Asthma (drug therapy)</term><term>Bronchioles (drug effects)</term><term>Bronchioles (physiology)</term><term>Bronchodilator Agents (pharmacology)</term><term>Calcium Signaling</term><term>Cells, Cultured</term><term>Drug Evaluation, Preclinical</term><term>Guinea Pigs</term><term>Humans</term><term>Imiquimod</term><term>Male</term><term>Myocytes, Smooth Muscle (drug effects)</term><term>Myocytes, Smooth Muscle (physiology)</term><term>Toll-Like Receptor 7 (agonists)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Aminoquinoléines (pharmacologie)</term><term>Animaux</term><term>Asthme (traitement médicamenteux)</term><term>Bronchioles ()</term><term>Bronchioles (physiologie)</term><term>Bronchodilatateurs (pharmacologie)</term><term>Cellules cultivées</term><term>Cochons d'Inde</term><term>Humains</term><term>Myocytes du muscle lisse ()</term><term>Myocytes du muscle lisse (physiologie)</term><term>Mâle</term><term>Récepteur de type Toll-7 (agonistes)</term><term>Signalisation du calcium</term><term>Évaluation préclinique de médicament</term></keywords><keywords scheme="MESH" type="chemical" qualifier="agonists" xml:lang="en"><term>Toll-Like Receptor 7</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Aminoquinolines</term><term>Bronchodilator Agents</term></keywords><keywords scheme="MESH" qualifier="agonistes" xml:lang="fr"><term>Récepteur de type Toll-7</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Bronchioles</term><term>Myocytes, Smooth Muscle</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Asthma</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Aminoquinoléines</term><term>Bronchodilatateurs</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Bronchioles</term><term>Myocytes du muscle lisse</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Bronchioles</term><term>Myocytes, Smooth Muscle</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Asthme</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Calcium Signaling</term><term>Cells, Cultured</term><term>Drug Evaluation, Preclinical</term><term>Guinea Pigs</term><term>Humans</term><term>Imiquimod</term><term>Male</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Bronchioles</term><term>Cellules cultivées</term><term>Cochons d'Inde</term><term>Humains</term><term>Myocytes du muscle lisse</term><term>Mâle</term><term>Signalisation du calcium</term><term>Évaluation préclinique de médicament</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Toll-like receptor (TLR) 7 agonists are known to reduce allergic airway inflammation. Their recently reported ability to rapidly relax airways has further increased their interest in the treatment of pulmonary disease. However, the mechanisms behind this effect are not fully understood. The present study, therefore, aimed to determine whether airway smooth muscle (ASM)-dependent mechanisms could be identified. TLR7 agonists were added to guinea pig airways following precontraction with carbachol in vitro or histamine in vivo. Pharmacological inhibitors were used to dissect conventional pathways of bronchodilation; tetrodotoxin was used or bilateral vagotomy was performed to assess neuronal involvement. Human ASM cells (HASMCs) were employed to determine the effect of TLR7 agonists on intracellular Ca(2+) ([Ca(2+)]i) mobilization. The well-established TLR7 agonist imiquimod rapidly relaxed precontracted airways in vitro and in vivo. This relaxation was demonstrated to be independent of nitric oxide, carbon monoxide, and cAMP signaling, as well as neuronal activity. A limited role for prostanoids could be detected. Imiquimod induced [Ca(2+)]i release from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca(2+)]i The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca(2+)]i This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca(2+)]i The effect is paralleled by other bronchorelaxant compounds, like chloroquine, which, like imiquimod, but unlike CL264, contains the chemical structure quinoline. Compounds with quinoline moieties may be of interest in the development of multifunctional drugs to treat pulmonary disease.</div></front></TEI><affiliations><list><country><li>Suède</li></country><region><li>Svealand</li></region><settlement><li>Stockholm</li></settlement></list><tree><noCountry><name sortKey="Kumlien Georen, Susanna" sort="Kumlien Georen, Susanna" uniqKey="Kumlien Georen S" first="Susanna" last="Kumlien Georén">Susanna Kumlien Georén</name><name sortKey="Starkhammar, Magnus" sort="Starkhammar, Magnus" uniqKey="Starkhammar M" first="Magnus" last="Starkhammar">Magnus Starkhammar</name></noCountry><country name="Suède"><region name="Svealand"><name sortKey="Larsson, Olivia J" sort="Larsson, Olivia J" uniqKey="Larsson O" first="Olivia J" last="Larsson">Olivia J. Larsson</name></region><name sortKey="Adner, Mikael" sort="Adner, Mikael" uniqKey="Adner M" first="Mikael" last="Adner">Mikael Adner</name><name sortKey="Cardell, Lars Olaf" sort="Cardell, Lars Olaf" uniqKey="Cardell L" first="Lars-Olaf" last="Cardell">Lars-Olaf Cardell</name><name sortKey="Fuchs, Barbara" sort="Fuchs, Barbara" uniqKey="Fuchs B" first="Barbara" last="Fuchs">Barbara Fuchs</name><name sortKey="Manson, Martijn L" sort="Manson, Martijn L" uniqKey="Manson M" first="Martijn L" last="Manson">Martijn L. Manson</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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