Toll 样受体 7 激动剂可快速有效舒张豚鼠气道。
Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs.
机构信息
Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, USA.
出版信息
J Allergy Clin Immunol. 2011 Feb;127(2):462-9. doi: 10.1016/j.jaci.2010.10.029. Epub 2010 Dec 17.
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.
背景
呼吸道病毒感染可导致哮喘恶化。Toll 样受体（TLR）7 是病毒单链 RNA 的受体，在肺部高表达。
目的
由于 TLR7 多态性与哮喘有关，我们研究了 TLR7 激动剂在豚鼠气道中的作用。
方法
我们通过电刺激迷走神经或静脉内给予乙酰胆碱在体内诱导豚鼠气道痉挛，并测量静脉内给予 TLR7 激动剂的作用。我们在离体豚鼠气管段中诱导气道平滑肌收缩，并测量 TLR7 激动剂、拮抗剂和相关信号通路的药理学抑制剂直接给予浴液的作用。
结果
TLR7 激动剂在给药后数分钟内即可急性抑制体内气道痉挛，并缓解气道平滑肌的收缩。TLR7 激动剂 R837（咪喹莫特）诱导的气道松弛被 TLR7 拮抗剂部分阻断，也被大电导、钙激活钾通道抑制剂；前列腺素合成抑制剂；和一氧化氮生成抑制剂阻断。另一种 TLR7 激动剂，21 -mer 单链硫代磷酸化聚尿嘧啶核苷酸（PolyUs），介导的松弛完全被 TLR7 拮抗剂阻断。
结论
这些数据表明了一种新的保护机制，可以限制呼吸道病毒感染期间的气道痉挛和维持气流。快速的时间框架与经典的 TLR7 信号不一致。R837 通过 TLR7 依赖和非依赖机制介导支气管扩张，而 PolyUs 仅通过 TLR7 依赖机制起作用。TLR7 非依赖机制涉及前列腺素和大电导、钙激活钾通道，而 TLR7 依赖机制涉及一氧化氮。TLR7 是一个有吸引力的治疗靶点，因为它能够在数分钟内逆转气道痉挛。
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