Paracellular permeability of bronchial epithelium is controlled by CFTR

Cell Physiol Biochem. 2011;28(2):289-96. doi: 10.1159/000331742. Epub 2011 Aug 16.

Abstract

In normal airway epithelium, the cystic fibrosis transmembrane conductance regulator (CFTR) transports Cl(-) ions to the apical surface of the epithelium paralleled by the flow of water through transcellular and paracellular pathways. The hypothesis was tested whether CFTR not only regulates the transcellular but also the paracellular shunt pathway. Therefore, we performed measurements of transepithelial electrical resistance (TER) and paracellular (14)C-mannitol permeability in wtCFTR (16HBE14o(-)) and delF508-CFTR (CFBE41o(-)) expressing human bronchial epithelial cells. Under resting conditions, CFBE41o(-) cell monolayers exhibit a higher paracellular permeability and lower TER as compared to 16HBE14o(-) monolayers. Stimulation of CFTR by cAMP induces opposite effects in the two cell lines. 16HBE14o(-) monolayers show a sharp decrease of TER, in parallel with a concomitant increase of paracellular permeability. The change in paracellular permeability is mediated by a myosin II dependent mechanism because it can be blocked by the myosin light chain kinase inhibitor ML-7. In contrast, CFBE41o(-) cells respond to cAMP stimulation with a decrease of paracellular permeability, paralleled by slight increase of TER. We conclude that stimulation of wtCFTR increases vectorial transcellular salt transport and, simultaneously, the paracellular permeability allowing water to follow through the paracellular pathway. In contrast, in CF epithelium cAMP stimulation increases neither vectorial salt transport nor paracellular permeability which is likely to contribute to the CF pulmonary phenotype. Taken together, our results link CFTR dysfunction to an improper regulation of the paracellular transport route.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azepines / pharmacology
  • Bronchi / cytology*
  • Cell Line
  • Cell Membrane Permeability / physiology*
  • Cyclic AMP / pharmacology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Epithelial Cells / physiology
  • Humans
  • Mannitol / metabolism
  • Mutation
  • Myosin-Light-Chain Kinase / antagonists & inhibitors
  • Myosin-Light-Chain Kinase / metabolism
  • Naphthalenes / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Tight Junctions / physiology

Substances

  • Azepines
  • Naphthalenes
  • Protein Kinase Inhibitors
  • ML 7
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Mannitol
  • Cyclic AMP
  • Myosin-Light-Chain Kinase