Airway Surface Liquid Volume Regulation Determines Different Airway Phenotypes in Liddle Compared with beta ENaC-overexpressing Mice

作者：Mall Marcus A^*; Button Brian; Johannesson Bjarki; Zhou Zhe; Livraghi Alessandra; Caldwell Ray A; Schubert Susanne C; Schultz Carsten; O'Neal Wanda K; Pradervand Sylvain; Hummler Edith; Rossier Bernard C; Grubb Barbara R; Boucher Richard C

来源：Journal of Biological Chemistry, 2010, 285(35): 26945-26955.

DOI：10.1074/jbc.M110.151803

Studies in cystic fibrosis patients and mice overexpressing the epithelial Na(+) channel beta-subunit (beta ENaC-Tg) suggest that raised airway Na(+) transport and airway surface liquid (ASL) depletion are central to the pathogenesis of cystic fibrosis lung disease. However, patients or mice with Liddle gain-of-function beta ENaC mutations exhibit hypertension but no lung disease. To investigate this apparent paradox, we compared the airway phenotype (nasal versus tracheal) of Liddle with CFTR-null, beta ENaC-Tg, and double mutant mice. In mouse nasal epithelium, the region that functionally mimics human airways, high levels of CFTR expression inhibited Liddle epithelial Na(+) channel (ENaC) hyperfunction. Conversely, in mouse trachea, low levels of CFTR failed to suppress Liddle ENaC hyperfunction. Indeed, Na(+) transport measured in Ussing chambers ("flooded" conditions) was raised in both Liddle and beta ENaC-Tg mice. Because enhanced Na(+) transport did not correlate with lung disease in these mutant mice, measurements in tracheal cultures under physiologic "thin film" conditions and in vivo were performed. Regulation of ASL volume and ENaC-mediated Na(+) absorption were intact in Liddle but defective in beta ENaC-Tg mice. We conclude that the capacity to regulate Na(+) transport and ASL volume, not absolute Na(+) transport rates in Ussing chambers, is the key physiologic function protecting airways from dehydration-induced lung disease.

• 出版日期2010-8-27