Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke

Mary Beth Brown, William R. Hunt, Julie E. Noe, Natalia I. Rush, Kelly S. Schweitzer, Thomas C. Leece, Aigul Moldobaeva, Elizabeth M. Wagner, Steven M. Dudek, Christophe Poirier, Robert Presson, Erich Gulbins, Irina Petrache

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Abnormal lung microvascular endothelial vascular barrier function may contribute to pulmonary inflammation, such as that occurring during inhalation of cigarette smoke (CS). Cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in both epithelial and endothelial cells, regulates the organization of tight junctions between epithelial cells and has also been implicated in the transport of sphingosine-1 phosphate (S1P), a vascular barrier–enhancing sphingolipid. Because CS has been shown to affect CFTR function, we hypothesized that CFTR function contributes to lung endothelial cell barrier and that CFTR dysfunction worsens CS-induced injury. CFTR inhibitors GlyH-101 or CFTRinh172 caused a dosedependent increase in pulmonary or bronchial endothelial monolayer permeability, which peaked after 4 hours. CFTR inhibition was associated with both intercellular gaps and actin stress fiber formation compared with vehicle-treated cells. Increasing endothelial S1P, either by exogenous treatment or by inhibition of its degradation, significantly improved the barrier function in CFTR-inhibited monolayers. Both cultured lung endothelia and the lung microcirculation visualized in vivo with intravital two-photon imaging of transgenic mice deficient in CFTR showed that CFTR dysfunction increased susceptibility to CS-induced permeability. These results suggested that CFTR function might be required for lung endothelial barrier, including adherence junction stability. Loss of CFTR function, especially concomitant to CS exposure, might promote lung inflammation by increasing endothelial cell permeability, which could be ameliorated by S1P.

Original languageEnglish (US)
Pages (from-to)260-268
Number of pages9
JournalPulmonary Circulation
Volume4
Issue number2
DOIs
StatePublished - Jun 1 2014

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Smoke
Tobacco Products
Endothelial Cells
Lung
Permeability
Blood Vessels
Pneumonia
Epithelial Cells
Stress Fibers
Sphingolipids
Tight Junctions
Microcirculation
Photons
Inhalation
Transgenic Mice
Endothelium
Anions
Actins

Keywords

  • Ceramides
  • COPD
  • Cystic fibrosis
  • S1P
  • Sphingolipids

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke. / Brown, Mary Beth; Hunt, William R.; Noe, Julie E.; Rush, Natalia I.; Schweitzer, Kelly S.; Leece, Thomas C.; Moldobaeva, Aigul; Wagner, Elizabeth M.; Dudek, Steven M.; Poirier, Christophe; Presson, Robert; Gulbins, Erich; Petrache, Irina.

In: Pulmonary Circulation, Vol. 4, No. 2, 01.06.2014, p. 260-268.

Research output: Contribution to journalArticle

Brown, Mary Beth ; Hunt, William R. ; Noe, Julie E. ; Rush, Natalia I. ; Schweitzer, Kelly S. ; Leece, Thomas C. ; Moldobaeva, Aigul ; Wagner, Elizabeth M. ; Dudek, Steven M. ; Poirier, Christophe ; Presson, Robert ; Gulbins, Erich ; Petrache, Irina. / Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke. In: Pulmonary Circulation. 2014 ; Vol. 4, No. 2. pp. 260-268.
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