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EDITORIAL FOCUS

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

Departments of ¹Anesthesiology, ³Pediatrics and Microbiology, and ⁴Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama; and ²Department of Pulmonary Medicine, Columbia University Medical Center, New York, New York

Submitted 18 November 2006 ; accepted in final form 9 April 2007

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

paramyxovirus; protein kinase C; G protein-coupled receptor kinase 2; CXCL8

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