TY - JOUR
T1 - Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia
AU - Moody, Mark
AU - Pennington, Carey
AU - Schultz, Carsten
AU - Caldwell, Ray
AU - Dinkel, Carlo
AU - Rossi, Michael W.
AU - McNamara, Sharon
AU - Widdicombe, Jonathan
AU - Gabriel, Sherif
AU - Traynor-Kaplan, Alexis E.
PY - 2005/9
Y1 - 2005/9
N2 - Amiloride-sensitive, epithelial Na+ channel (ENaC)-mediated, active absorption of Na+ is elevated in the airway epithelium of cystic fibrosis (CF) patients, resulting in excess fluid removal from the airway lumen. This excess fluid/volume absorption corresponds to CF transmembrane regulator-linked defects in ENaC regulation, resulting in the reduced mucociliary clearance found in CF airways. Herein we show that INO-4995, a synthetic analog of the intracellular signaling molecule, D-myo-inositol 3,4,5,6-tetrakisphosphate, inhibits Na+ and fluid absorption across CF airway epithelia, thus alleviating this critical pathology. This conclusion was based on electrophysiological studies, fluid absorption, and 22Na+ flux measurements in CF airway epithelia, contrasted with normal epithelia, and on electrophysiological studies in Madin-Darby canine kidney cells and 3T3 cells overexpressing ENaC. The effects of INO-4995 were long-lasting, dose-dependent, and more pronounced in epithelia from CF patients vs. controls. These findings support preclinical development of INO-4995 for CF treatment and demonstrate for the first time the therapeutic potential of inositol polyphosphate derivatives.
AB - Amiloride-sensitive, epithelial Na+ channel (ENaC)-mediated, active absorption of Na+ is elevated in the airway epithelium of cystic fibrosis (CF) patients, resulting in excess fluid removal from the airway lumen. This excess fluid/volume absorption corresponds to CF transmembrane regulator-linked defects in ENaC regulation, resulting in the reduced mucociliary clearance found in CF airways. Herein we show that INO-4995, a synthetic analog of the intracellular signaling molecule, D-myo-inositol 3,4,5,6-tetrakisphosphate, inhibits Na+ and fluid absorption across CF airway epithelia, thus alleviating this critical pathology. This conclusion was based on electrophysiological studies, fluid absorption, and 22Na+ flux measurements in CF airway epithelia, contrasted with normal epithelia, and on electrophysiological studies in Madin-Darby canine kidney cells and 3T3 cells overexpressing ENaC. The effects of INO-4995 were long-lasting, dose-dependent, and more pronounced in epithelia from CF patients vs. controls. These findings support preclinical development of INO-4995 for CF treatment and demonstrate for the first time the therapeutic potential of inositol polyphosphate derivatives.
KW - Epithelial Na channels
KW - Fluid absorption
UR - http://www.scopus.com/inward/record.url?scp=23944522759&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23944522759&partnerID=8YFLogxK
U2 - 10.1152/ajpcell.00591.2004
DO - 10.1152/ajpcell.00591.2004
M3 - Article
C2 - 15857902
AN - SCOPUS:23944522759
SN - 0363-6143
VL - 289
SP - C512-C520
JO - American Journal of Physiology - Cell Physiology
JF - American Journal of Physiology - Cell Physiology
IS - 3 58-3
ER -