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首页> 外文期刊>American Journal of Physiology >Respiratory syncytial virus induces airway insensitivity to beta-agonists in BALB/c mice.
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Respiratory syncytial virus induces airway insensitivity to beta-agonists in BALB/c mice.

机译：呼吸道合胞病毒在BALB / c小鼠中诱导呼吸道对β激动剂不敏感。

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beta-Adrenergic agonists (beta-agonists) are commonly used to treat respiratory syncytial virus (RSV) bronchiolitis but are generally ineffective for unknown reasons. We have previously shown that RSV strain A2 inhibits bronchoalveolar epithelial responses to beta-agonists in a BALB/c mouse model by inducing heterologous keratinocyte cytokine (KC)/CXCR2-mediated desensitization of epithelial beta(2)-adrenergic receptors. The aim of the current study was to determine whether RSV also induces airway insensitivity to beta-agonists. Total lung resistance (R) was measured in anesthetized female BALB/c mice undergoing mechanical ventilation on a flexiVent computer-controlled piston ventilator. Data were analyzed using the single-compartment model. Infection with RSV A2 did not induce airway hyperresponsiveness to increasing doses of the nebulized cholinergic agonist methacholine (MCh) at any time point after RSV infection. Prenebulization with the beta-agonist terbutaline (100 muM) significantly attenuated bronchoconstrictive responses to 20 and 50 mg/ml MCh in uninfected mice and in mice infected with RSV 4-8 days postinfection (d.p.i.). However, in mice infected with replication-competent, but not UV-inactivated, RSV for 2 days, significant terbutaline insensitivity was found. Terbutaline insensitivity at 2 d.p.i. could be reversed by systemic preinfection treatment with neutralizing anti-CXCR2 antibodies, which reduced bronchoalveolar lavage (BAL) neutrophil counts but did not alter viral replication, BAL KC levels, or lung edema. Terbutaline insensitivity was also reversed by postinfection nebulization with neutralizing anti-KC or anti-CXCR2 antibodies and could be replicated in normal, uninfected mice by nebulization with recombinant KC. These data suggest that KC/CXCR2-mediated airway insensitivity to beta-agonists may underlie the modest utility of these drugs as bronchodilators in therapy for acute RSV bronchiolitis.
机译：β-肾上腺素能激动剂（β-激动剂）通常用于治疗呼吸道合胞病毒（RSV）细支气管炎，但由于未知原因通常无效。我们以前已经表明，RSV菌株A2通过诱导异源角化细胞细胞因子（KC）/ CXCR2介导的上皮β（2）-肾上腺素能受体脱敏作用，抑制BALB / c小鼠模型中支气管肺泡上皮对β-激动剂的反应。当前研究的目的是确定RSV是否也诱导气道对β激动剂不敏感。在麻醉的雌性BALB / c小鼠中，在柔性计算机控制的活塞呼吸机上进行机械通气，测量总肺阻力（R）。使用单室模型分析数据。在RSV感染后的任何时间点，感染RSV A2均不会引起呼吸道对增加剂量的雾化胆碱能激动剂乙酰甲胆碱（MCh）的气道高反应性。在未感染的小鼠和感染后4-8天感染RSV的小鼠中，用β-激动剂特布他林（100μM）进行的预雾化显着减弱了对20和50 mg / ml MCh的支气管收缩反应。但是，在具有复制能力但未被紫外线灭活的RSV感染2天的小鼠中，发现了明显的特布他林不敏感性。在d.p.i时对terbutaline不敏感可以通过用中和性抗CXCR2抗体进行全身性预感染治疗来逆转，这可以减少支气管肺泡灌洗（BAL）中性粒细胞计数，但不会改变病毒复制，BAL KC水平或肺水肿。通过用中和抗KC或抗CXCR2抗体进行感染后雾化也可以逆转特布他林的不敏感性，并且可以通过用重组KC雾化在正常的，未感染的小鼠中复制特布他林。这些数据表明，KC / CXCR2介导的气道对β受体激动剂不敏感可能是这些药物作为支气管扩张剂在急性RSV细支气管炎治疗中的适度应用的基础。

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