期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 293, 期 2, 页码 L281-L289出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00458.2006
关键词
paramyxovirus; protein kinase C; G protein-coupled receptor kinase 2; CXCL8
资金
- NCRR NIH HHS [K01 RR017626, K01 RR017626-02, RR-17626, K01 RR017626-03, K01 RR017626-04] Funding Source: Medline
- NHLBI NIH HHS [R01 HL031197, R01 HL066211, R01 HL051173, R37 HL031197, HL-51173, HL-31197, HL-071042, HL-066211, R01 HL071042] Funding Source: Medline
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 PKC gamma 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 PKC zeta 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.
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