Novel role for CFTR in fluid absorption from the distal airspaces of the lung.
Novel role for CFTR in fluid absorption from the distal airspaces of the lung.
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CFTR在肺部远端空域吸收流体吸收中的新作用。
DOI：
10.1085/jgp.119.2.199
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发表时间：
2002-02
影响因子：
3.8
通讯作者：
Matthay, M A
中科院分区：
文献类型：
--
作者：
Fang, X;Fukuda, N;Barbry, P;Sartori, C;Verkman, A S;Matthay, M A
肺泡内液体的主动吸收对临床肺水肿的消退具有重要意义。虽然Na~+通道是Na~+吸收的主要途径，但Cl~+-−转运途径尚不清楚。我们应用了一系列互补的方法来确定氯−转运在完整小鼠肺远端空气中液体清除中的作用，使用的是野生型和囊性纤维化ΔF508小鼠。对野生型小鼠的初步研究表明，氯−通道抑制剂和氯−离子替代显著抑制液体清除，为氯−跨细胞转运提供了证据。作为对异丙肾上腺素刺激cAMP的反应，CFTR抑制剂格列本脲抑制了野生型小鼠和正常人类肺的清除。虽然异丙肾上腺素显著增加野生型小鼠的液体吸收，但对ΔF508小鼠没有影响。在23°C(阻断主动液体吸收)下进行的放射性同位素清除研究显示，在没有和有异丙肾上腺素的情况下，∼在30分钟内清除22nA的20%。在野生型小鼠中，异丙肾上腺素可使~(36)Cl的清除量增加47%，而在ΔF508小鼠中则无明显变化，为cAMP刺激的Cl-−转运提供了独立的证据。此外，在急性容量超负荷性肺水肿的小鼠模型中，CFTR在液体清除方面发挥了主要作用。注入40%体重的生理盐水后，野生型小鼠的肺湿/干重比增加了28%，而ΔF508小鼠的肺湿/干重比增加了28%。这些结果为CFTR在肺远端空隙中的重要作用提供了直接证据。
The active absorption of fluid from the airspaces of the lung is important for the resolution of clinical pulmonary edema. Although ENaC channels provide a major route for Na+ absorption, the route of Cl− transport has been unclear. We applied a series of complementary approaches to define the role of Cl− transport in fluid clearance in the distal airspaces of the intact mouse lung, using wild-type and cystic fibrosis ΔF508 mice. Initial studies in wild-type mice showed marked inhibition of fluid clearance by Cl− channel inhibitors and Cl− ion substitution, providing evidence for a transcellular route for Cl− transport. In response to cAMP stimulation by isoproterenol, clearance was inhibited by the CFTR inhibitor glibenclamide in both wild-type mice and the normal human lung. Although isoproterenol markedly increased fluid absorption in wild-type mice, there was no effect in ΔF508 mice. Radioisotopic clearance studies done at 23°C (to block active fluid absorption) showed ∼20% clearance of 22Na in 30 min both without and with isoproterenol. However, the clearance of 36Cl was increased by 47% by isoproterenol in wild-type mice but was not changed in ΔF508 mice, providing independent evidence for involvement of CFTR in cAMP-stimulated Cl− transport. Further, CFTR played a major role in fluid clearance in a mouse model of acute volume-overload pulmonary edema. After infusion of saline (40% body weight), the lung wet-to-dry weight ratio increased by 28% in wild-type versus 64% in ΔF508 mice. These results provide direct evidence for a functionally important role for CFTR in the distal airspaces of the lung.