Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia

Mark Moody, Carey Pennington, Carsten Schultz, Ray Caldwell, Carlo Dinkel, Michael W. Rossi, Sharon McNamara, Jonathan Widdicombe, Sherif Gabriel, Alexis E. Traynor-Kaplan

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume289
Issue number3 58-3
DOIs
StatePublished - Sep 2005
Externally publishedYes

Fingerprint

Polyphosphates
Inositol
Hydrodynamics
Fluid dynamics
Cystic Fibrosis
Epithelial Sodium Channels
Epithelium
Derivatives
Fluids
Bridge clearances
Amiloride
Pathology
Mucociliary Clearance
3T3 Cells
Madin Darby Canine Kidney Cells
Fluxes
Defects
Molecules
INO-4995
Therapeutics

Keywords

  • Epithelial Na channels
  • Fluid absorption

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia. / Moody, Mark; Pennington, Carey; Schultz, Carsten; Caldwell, Ray; Dinkel, Carlo; Rossi, Michael W.; McNamara, Sharon; Widdicombe, Jonathan; Gabriel, Sherif; Traynor-Kaplan, Alexis E.

In: American Journal of Physiology - Cell Physiology, Vol. 289, No. 3 58-3, 09.2005.

Research output: Contribution to journalArticle

Moody, M, Pennington, C, Schultz, C, Caldwell, R, Dinkel, C, Rossi, MW, McNamara, S, Widdicombe, J, Gabriel, S & Traynor-Kaplan, AE 2005, 'Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia', American Journal of Physiology - Cell Physiology, vol. 289, no. 3 58-3. https://doi.org/10.1152/ajpcell.00591.2004
Moody, Mark ; Pennington, Carey ; Schultz, Carsten ; Caldwell, Ray ; Dinkel, Carlo ; Rossi, Michael W. ; McNamara, Sharon ; Widdicombe, Jonathan ; Gabriel, Sherif ; Traynor-Kaplan, Alexis E. / Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia. In: American Journal of Physiology - Cell Physiology. 2005 ; Vol. 289, No. 3 58-3.
@article{34b01301321a4c51966c0845d11fa404,
title = "Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia",
abstract = "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.",
keywords = "Epithelial Na channels, Fluid absorption",
author = "Mark Moody and Carey Pennington and Carsten Schultz and Ray Caldwell and Carlo Dinkel and Rossi, {Michael W.} and Sharon McNamara and Jonathan Widdicombe and Sherif Gabriel and Traynor-Kaplan, {Alexis E.}",
year = "2005",
month = "9",
doi = "10.1152/ajpcell.00591.2004",
language = "English (US)",
volume = "289",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "3 58-3",

}

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

VL - 289

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 3 58-3

ER -