Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of G_q protein–dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological G_q inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of G_q, was effective in silencing G_q signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective G_q inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of G_q proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease.

阻塞性肺病是全世界残疾和死亡的常见原因。一个标志性特征是 G _q蛋白依赖性信号级联的异常激活。目前，靶向单一 G 蛋白（异三聚体鸟嘌呤核苷酸结合蛋白）偶联受体 (GPCRs) 的药物用于降低气道张力。然而，治疗效果通常是有限的，因为各种 GPCR 会导致支气管收缩，而长期暴露于受体激活药物会导致脱敏。因此，我们假设药理学 G _q抑制可以作为实现有效治疗性支气管松弛的中心机制。我们发现化合物 FR900359 (FR) 是 G _q的膜渗透抑制剂，可有效沉默 G_q小鼠和人类气道平滑肌细胞中的信号传导。此外，FR 既能防止支气管收缩反应，又能在小鼠、猪和人类气道组织中引发持续的气道松弛。在健康的野生型小鼠中吸入 FR 会导致该化合物在肺部的局部浓度很高，并防止气道收缩，而不会对血压和心率产生急性影响。在使用卵清蛋白和屋尘螨作为过敏原的过敏原致敏小鼠模型中，FR 给药还可以防止气道过度反应。我们的研究结果表明，当局部应用于体内小鼠气道时，FR 是一种选择性 G _{q抑制剂，并表明 G q的药理学阻断}蛋白质可能是实现哮喘性肺病支气管松弛的有用治疗策略。