title: The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation.
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.
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Olivia J
authors.initials: OJ
authors.lastname: Larsson
authors.affiliation: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Martijn L
authors.initials: ML
authors.lastname: Manson
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Magnus
authors.initials: M
authors.lastname: Starkhammar
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden;
authors.forename: Barbara
authors.initials: B
authors.lastname: Fuchs
authors.affiliation: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Susanna
authors.initials: S
authors.lastname: Kumlien Georén
authors.affiliation: Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Department of ENT Disease, Karolinska University Hospital, Stockholm, Sweden; lars-olaf.cardell@ki.se.
authors.forename: Lars-Olaf
authors.initials: LO
authors.lastname: Cardell
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D055745:Bronchioles / Q000187:drug effects / Q000502:physiology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D020013:Calcium Signaling; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006801:Humans; D000077271:Imiquimod; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000819:agonists*
chemical_list: D000634:Aminoquinolines; D001993:Bronchodilator Agents; D051199:Toll-Like Receptor 7; D000077271:Imiquimod
keywords: asthma; bronchodilation; imiquimod; quinoline; toll-like receptor 7