title: Respiratory syncytial virus induces insensitivity to beta-adrenergic agonists in mouse lung epithelium in vivo.
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 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 PKCzeta 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 PKCzeta 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.
authors: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35205-3703, USA.
authors: Ian C
authors: IC
authors: Davis
authors: Anna
authors: A
authors: Xu
authors: Zhiqian
authors: Z
authors: Gao
authors: Judy M
authors: JM
authors: Hickman-Davis
authors: Phillip
authors: P
authors: Factor
authors: Wayne M
authors: WM
authors: Sullender
authors: Sadis
authors: S
authors: Matalon
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D015633:Extravascular Lung Water / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000821:virology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism*; D018113:Respiratory Syncytial Virus, Human / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D013726:Terbutaline / Q000494:pharmacology; D000099221:Protein Kinase C zeta
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D005576:Colforsin; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D018343:Receptors, Adrenergic, beta-2; D013726:Terbutaline; D000099221:Protein Kinase C zeta; C475895:Cxcl1 protein, mouse