Singh Divyendu, McCann Kelly L, Imani Farhad
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Am J Physiol Lung Cell Mol Physiol. 2007 Aug;293(2):L436-45. doi: 10.1152/ajplung.00097.2007. Epub 2007 Jun 8.
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.
呼吸道合胞病毒（RSV）是婴儿细支气管炎的主要病因，RSV感染的一个常见特征是肺通透性增加。感染的肺部液体蓄积是由内皮和上皮细胞膜完整性的改变引起的。然而，病毒诱导液体外渗的确切机制仍不清楚。在此，我们报告，用RSV感染人上皮细胞会导致显著的上皮膜屏障破坏，这通过跨上皮电阻（TEpR）的降低来评估。TEpR的这种降低表明细胞旁通透性的改变，是由明显的细胞细胞骨架重排介导的。重要的是，使用p38丝裂原活化蛋白激酶抑制剂（SB - 203580）可减弱TEpR的降低，但JNK抑制剂SP - 600125对其有部分影响。有趣的是，在没有RSV感染的情况下，用MEK1/2抑制剂（U - 0126）处理A549细胞会导致TEpR降低。TEpR的变化与热休克蛋白27（Hsp27）磷酸化增加以及肌动蛋白微丝重排同时发生。因此，我们的数据表明，p38丝裂原活化蛋白激酶和Hsp27是RSV诱导人上皮膜通透性所必需的。
