title: Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke.
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 dose-dependent 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.
authors.affiliation: Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA ; Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Brown
authors.affiliation: Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Hunt
authors.affiliation: Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Noe
authors.affiliation: Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Rush
authors.affiliation: Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Schweitzer
authors.affiliation: Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Leece
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Aigul
authors.initials: A
authors.lastname: Moldobaeva
authors.affiliation: Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wagner
authors.affiliation: Department of Medicine, University of Illinois, Chicago, Illinois, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.affiliation: Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Poirier
authors.affiliation: Department of Anesthesia, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Presson
authors.affiliation: Department of Anesthesia, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana, USA ; Richard L. Roudebush Veteran Affairs Medical Center, Indianapolis, Indiana, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
keywords: COPD; S1P; ceramides; cystic fibrosis; sphingolipids