Respiratory syncytial virus induces insensitivity to β-adrenergic agonists in mouse lung epithelium in vivo

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Abstract
Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants and children worldwide. We wished to determine whether intratracheal administration of β-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 β-agonists had no effect at either day 2 or day 4. Insensitivity to β-agonists was not a result of elevated plasma catecholamines or lung epithelial cell β-adrenergic receptor degradation. Instead, RSV-infected mice had significantly higher levels of phosphorylated PKCζ in the membrane fractions of their lung epithelial cells. In addition, insensitivity to β-agonists was mediated in a paracrine fashion by KC (the murine homolog of CXCL8) and reversed by inhibition of either PKCζ or G protein-coupled receptor kinase 2 (GRK2). These results indicate that insufficient response to β-agonists in RSV may be caused, at least in part, by impaired β-adrenergic receptor signaling, as a consequence of GRK2-mediated uncoupling of β-adrenergic receptors from adenylyl cyclase.