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This Article Full Text Full Text (PDF) All Versions of this Article: 293/2/L281    most recent 00458.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Davis, I. C. Articles by Matalon, S. Search for Related Content PubMed PubMed Citation Articles by Davis, I. C. Articles by Matalon, S.

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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