Airway surface fluid volume and Cl content in cystic fibrosis and normal bronchial xenografts

Abstract

We describe the use of an in vivo human bronchial xenograft model of cystic fibrosis (CF) and non-CF airways to investigate pathophysiological alterations in airway surface fluid (ASF) volume (V(s)) and Cl content. V(s) was calculated based on the dilution of an impermeable marker, [3H]inulin, during harvesting of ASF from xenografts with an isosmotic Cl-free solution. These calculations demonstrated that V(s) in CF xenographs (28 ± 3.0 μl/cm2; n = 17) was significantly less than that of non-CF xenografts (35 ± 2.4 μl/cm2; n = 30). The Cl concentration of ASF ([Cl](s)) was determined using a solid-state AgCl electrode and adjusted for dilution during harvesting using the impermeable [3H]inulin marker. Cumulative results demonstrate small but significant elevations (P < 0.045) in [Cl](s) in CF (125 ± 4 mM; n = 27) compared with non-CF (114 ± 4 mM; n = 48) xenografts. To investigate potential mechanisms by which CF airways may facilitate a higher level of fluid absorption yet retain slightly elevated levels of Cl, we sought to evaluate the capacity of CF and non-CF airways to absorb both 22Na and 36Cl. Two consistent findings were evident from these studies. First, in both CF and non-CF xenografts, 22Na and 36Cl were always absorbed in an equal molar ratio. Second, CF xenografts hyperabsorbed (~1.5-fold higher) both 22Na and 36Cl compared with non- CF xenografts. These results substantiate previously documented findings of elevated Na absorption in CF airways and also suggest that the slightly elevated [Cl](s) found in this study of CF xenograft epithelia does not occur through a mechanism of decreased apical permeability to Cl.