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Respiratory Syncytial Virus Infection Reduces ₂-Adrenergic Responses in Human Airway Smooth Muscle

Departments of Pediatrics and Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and Department of Pediatrics, The Ohio State University, Columbus, Ohio

Correspondence and requests for reprints should be addressed to Dr. Paul E. Moore, Vanderbilt University School of Medicine, 2200 Children's Way, 11215 Doctor's Office Tower, Nashville, TN 37232–9500. E-mail: paul.moore{at}vanderbilt.edu

Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract illness in infants, the effect of RSV on human airway smooth muscle (HASM) has not been studied. We hypothesized that RSV has direct effects on cAMP formation and ₂-adrenergic receptor (ADRB2) density and that ADRB2 haplotype influences this response. A recombinant green-fluorescent protein (rg) expressing RSV was used to determine whether RSV could infect cultured HASM. Influence of RSV infection on ₂-adrenergic responsiveness was determined by measuring differences in isoproterenol (ISO)-induced cyclic AMP (cAMP) formation, ADRB2 density, and G_i expression in HASM cells challenged with RSV, with ultraviolet-inactivated RSV, and with mock infection. The rgRSV efficiently infected cultured HASM cells. ISO-induced cAMP formation was significantly reduced in cells infected with RSV, compared with mock-infected and ultraviolet-inactivated RSV, in a time- and concentration-dependent manner. Forskolin-induced cAMP formation and Gi expression were not altered in cells infected with RSV, suggesting that the influence of RSV on ₂-adrenergic relaxation was upstream of cAMP formation. ADRB2 density was reduced in cells infected with RSV, compared with mock infection, and the Arg16Gln27 ADRB2 haplotype was associated with decreased ISO-induced cAMP formation (P < 0.05) and with decreased ADRB2 density at baseline (P < 0.05). The implications of these results are that limitations of ₂-agonists in the treatment of any airway obstruction associated with RSV infection may be related to direct effects of RSV on HASM, and ADRB2 genotype may predict ₂-adrenergic responses.

Key Words: ₂-adrenergic receptor • haplotype • human airway smooth muscle • isoproterenol • respiratory syncytial virus

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