Respiratory syncytial virus induces insensitivity to beta-adrenergic agonists in mouse lung epithelium in vivo.
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.
Davis
Ian C
IC
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, AL 35205-3703, USA.
Xu
Anna
A
Gao
Zhiqian
Z
Hickman-Davis
Judy M
JM
Factor
Phillip
P
Sullender
Wayne M
WM
Matalon
Sadis
S
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
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