MAPK and heat shock protein 27 activation are associated with respiratory syncytial virus induction of human bronchial epithelial monolayer disruption.
Respiratory syncytial virus (RSV) is the major cause of bronchiolitis in infants, and a common feature of RSV infections is increased lung permeability. The accumulation of fluid in the infected lungs is caused by changes in the endothelial and epithelial membrane integrity. However, the exact mechanisms of viral-induced fluid extravasation remain unclear. Here, we report that infection of human epithelial cells with RSV results in significant epithelial membrane barrier disruption as assessed by a decrease in transepithelial electrical resistance (TEpR). This decrease in TEpR, which indicates changes in paracellular permeability, was mediated by marked cellular cytoskeletal rearrangement. Importantly, the decrease in TEpR was attenuated by using p38 MAPK inhibitors (SB-203580) but was partially affected by JNK inhibitor SP-600125. Interestingly, treatment of A549 cells with MEK1/2 inhibitor (U-0126) led to a decrease in TEpR in the absence of RSV infection. The changes in TEpR were concomitant with an increase in heat shock protein 27 (Hsp27) phosphorylation and with actin microfilament rearrangement. Thus our data suggest that p38 MAPK and Hsp27 are required for RSV induction of human epithelial membrane permeability.
Singh
Divyendu
D
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
McCann
Kelly L
KL
Imani
Farhad
F
D017209:Apoptosis; D001980:Bronchi / Q000166:cytology; D002199:Capillary Permeability / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D015633:Extravascular Lung Water / Q000378:metabolism / Q000821:virology; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology* / Q000821:virology*; D018357:Respiratory Syncytial Virus Infections / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; C482128:MAP2K2 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2