Respiratory syncytial virus induces insensitivity to β-adrenergic agonists in mouse lung epithelium in vivo
Respiratory syncytial virus induces insensitivity to β-adrenergic agonists in mouse lung epithelium in vivo
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DOI：
10.1152/ajplung.00458.2006
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发表时间：
2007-08-01
影响因子：
4.9
通讯作者：
Matalon, Sadis
中科院分区：
文献类型：
--
作者：
Davis, Ian C.;Xu, Anna;Matalon, Sadis
呼吸道合胞病毒（RSV）是全球婴儿和儿童毛细支气管炎的最常见原因。我们希望确定肺内注射β-受体激动剂是否能改善RSV感染小鼠远端呼吸道上皮的肺泡液清除率（AFC）。用RSV毒株A2鼻内感染后，通过向依赖性肺中滴注5% BSA，在麻醉、通气的BALB/c小鼠中测量AFC。我们发现，直接激活蛋白激酶A毛喉素或8-溴-cAMP增加AFC在感染RSV后第2天。相比之下，短效和长效β受体激动剂在第2天或第4天没有效果。对β-受体激动剂不敏感不是血浆儿茶酚胺升高或肺上皮细胞β-肾上腺素能受体降解的结果。相反，RSV感染的小鼠在其肺上皮细胞的膜组分中具有显著更高水平的磷酸化PKC γ。此外，对β-激动剂的不敏感性由KC（CXCL 8的鼠同系物）以旁分泌方式介导，并通过抑制PKC zeta或G蛋白偶联受体激酶2（GRK 2）来逆转。这些结果表明，RSV中对β-激动剂的反应不足可能至少部分由受损的β-肾上腺素能受体信号传导引起，这是GRK 2介导的β-肾上腺素能受体与腺苷酸环化酶解偶联的结果。
Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants and children worldwide. We wished to determine whether intratracheal administration of beta-agonists improved alveolar fluid clearance (AFC) across the distal respiratory epithelium of RSV-infected mice. Following intranasal infection with RSV strain A2, AFC was measured in anesthetized, ventilated BALB/c mice by instillation of 5% BSA into the dependent lung. We found that direct activation of protein kinase A by forskolin or 8-bromo-cAMP increased AFC at day 2 after infection with RSV. In contrast, short-and long-acting beta-agonists had no effect at either day 2 or day 4. Insensitivity to beta-agonists was not a result of elevated plasma catecholamines or lung epithelial cell beta-adrenergic receptor degradation. Instead, RSV-infected mice had significantly higher levels of phosphorylated PKC gamma in the membrane fractions of their lung epithelial cells. In addition, insensitivity to beta-agonists was mediated in a paracrine fashion by KC (the murine homolog of CXCL8) and reversed by inhibition of either PKC zeta or G protein-coupled receptor kinase 2 (GRK2). These results indicate that insufficient response to beta-agonists in RSV may be caused, at least in part, by impaired beta-adrenergic receptor signaling, as a consequence of GRK2-mediated uncoupling of beta-adrenergic receptors from adenylyl cyclase.