Gallacher M, Brown S G, Hale B G, Fearns R, Olver R E, Randall R E, Wilson S M
Centre for Cardiovascular and Lung Research, University of Dundee, UK.
J Physiol. 2009 Jul 1;587(Pt 13):3159-73. doi: 10.1113/jphysiol.2009.171223. Epub 2009 Apr 29.
Influenza A viruses cause lung disease via an incompletely understood mechanism that involves the accumulation of liquid within the lungs. The accumulation of lung liquid is normally prevented by epithelial Na(+) absorption, a transport process regulated via several pathways including phosphoinositide-3-kinase (PI3K). Since the influenza A virus encodes a non-structural protein (NS1) that can activate this kinase, we now explore the effects of NS1 upon the biophysical properties of human airway epithelial cells. Transient expression of NS1 depolarized electrically isolated cells maintained in glucocorticoid-free medium by activating a cation conductance identical to the glucocorticoid-induced conductance seen in single cells. This response involved PI3K-independent and PI3K-dependent mechanisms. Infecting glucocorticoid-deprived cells with influenza A virus disrupted the normal electrical coupling between neighbouring cells, but also activated a conductance identical to that induced by NS1. This response to virus infection was only partially dependent upon NS1-mediated activation of PI3K. The presence of NS1 allows influenza A to modify the biophysical properties of infected cells by activating a Na(+)-permeable conductance. Whilst the activation of Na(+)-permeable channels may be expected to increase the rate of Na(+) absorption and thus reduce the volume of liquid in the lung, liquid does normally accumulate in influenza A-infected lungs. The overall effect of influenza A on lung liquid volume may therefore reflect a balance between the activation and inhibition of Na(+)-permeable channels.
甲型流感病毒通过一种尚未完全了解的机制引发肺部疾病，该机制涉及肺内液体的积聚。肺内液体的积聚通常可通过上皮钠（Na⁺）吸收来防止，这是一种通过包括磷酸肌醇-3-激酶（PI3K）在内的多种途径调节的转运过程。由于甲型流感病毒编码一种可激活该激酶的非结构蛋白（NS1），我们现在探讨NS1对人气道上皮细胞生物物理特性的影响。NS1的瞬时表达通过激活一种与单细胞中糖皮质激素诱导的电导相同的阳离子电导，使维持在无糖皮质激素培养基中的电隔离细胞去极化。这种反应涉及不依赖PI3K和依赖PI3K的机制。用甲型流感病毒感染缺乏糖皮质激素的细胞会破坏相邻细胞之间的正常电偶联，但也会激活一种与NS1诱导的电导相同的电导。这种对病毒感染的反应仅部分依赖于NS1介导的PI3K激活。NS1的存在使甲型流感病毒能够通过激活一种Na⁺通透性电导来改变受感染细胞的生物物理特性。虽然激活Na⁺通透性通道可能会增加Na⁺吸收速率，从而减少肺内液体量，但在甲型流感病毒感染的肺中液体通常会积聚。因此，甲型流感病毒对肺内液体量的总体影响可能反映了Na⁺通透性通道激活与抑制之间的平衡。
