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The TLR7 agonist imiquimod induces bronchodilation via a nonneuronal TLR7-independent mechanism: a possible role for quinoline in airway dilation
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- Larsson, OJ (författare)
- Karolinska Institutet
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- Manson, ML (författare)
- Karolinska Institutet
- Starkhammar, M (författare)
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- Fuchs, B (författare)
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- (creator_code:org_t)
- American Physiological Society, 2016
- 2016
- Engelska.
- Ingår i: American journal of physiology. Lung cellular and molecular physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 310:11, s. L1121-L1129
- Tidskriftsartikel (refereegranskat)
Abstract
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- 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 Ca2+([Ca2+]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 [Ca2+]irelease from endoplasmic reticulum stores in HASMCs, inhibiting histamine-induced [Ca2+]i. The TLR7 antagonist IRS661 failed to inhibit relaxation, and the structurally dissimilar agonist CL264 did not relax airways or inhibit [Ca2+]i. This study shows that imiquimod acts directly on ASM to induce bronchorelaxation, via a TLR7-independent release of [Ca2+]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.
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- Larsson, OJ
- Manson, ML
- Starkhammar, M
- Fuchs, B
- Adner, M
- Georen, SK
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- Cardell, LO
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