Mechanisms of lung endothelial barrier disruption induced by cigarette

Kelly S. Schweitzer, Hadi Hatoum, Mary Beth Brown, Mehak Gupta, Matthew J. Justice, Besem Beteck, Mary van Demark, Yuan Gu, Robert Presson, Walter C. Hubbard, Irina Petrache

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The epithelial and endothelial cells lining the alveolus form a barrier essential for the preservation of the lung respiratory function, which is, however, vulnerable to excessive oxidative, inflammatory, and apoptotic insults. Whereas profound breaches in this barrier function cause pulmonary edema, more subtle changes may contribute to inflammation. The mechanisms by which cigarette smoke (CS) exposure induce lung inflammation are not fully understood, but an early alteration in the epithelial barrier function has been documented. We sought to investigate the occurrence and mechanisms by which soluble components of mainstream CS disrupt the lung endothelial cell barrier function. Using cultured primary rat microvascular cell monolayers, we report that CS induces endothelial cell barrier disruption in a dose- and time-dependent manner of similar magnitude to that of the epithelial cell barrier. CS exposure triggered a mechanism of neutral sphingomyelinase-mediated ceramide upregulation and p38 MAPK and JNK activation that were oxidative stress dependent and that, along with Rho kinase activation, mediated the endothelial barrier dysfunction. The morphological changes in endothelial cell monolayers induced by CS included actin cytoskeletal rearrangement, junctional protein zonula occludens-1 loss, and intercellular gap formation, which were abolished by the glutathione modulator N-acetylcysteine and ameliorated by neutral sphingomyelinase inhibition. The direct application of ceramide recapitulated the effects of CS, by disrupting both endothelial and epithelial cells barrier, by a mechanism that was redox and apoptosis independent and required Rho kinase activation. Furthermore, ceramide induced dose-dependent alterations of alveolar microcirculatory barrier in vivo, measured by two-photon excitation microscopy in the intact rat. In conclusion, soluble components of CS have direct endothelial barrierdisruptive effects that could be ameliorated by glutathione modulators or by inhibitors of neutral sphingomyelinase, p38 MAPK, JNK, and Rho kinase. Amelioration of endothelial permeability may alleviate lung and systemic vascular dysfunction associated with smoking-related chronic obstructive lung diseases.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume301
Issue number6
DOIs
StatePublished - Dec 2011

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Smoke
Tobacco Products
Lung
Sphingomyelin Phosphodiesterase
Endothelial Cells
rho-Associated Kinases
Ceramides
Epithelial Cells
p38 Mitogen-Activated Protein Kinases
Glutathione
Zonula Occludens-1 Protein
MAP Kinase Kinase 4
Mitogen-Activated Protein Kinase Kinases
Acetylcysteine
Pulmonary Edema
Photons
Chronic Obstructive Pulmonary Disease
Oxidation-Reduction
Blood Vessels
Actins

Keywords

  • Antioxidants
  • Cell death
  • Cytoskeleton
  • Inflammation
  • Sphingolipids

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

Mechanisms of lung endothelial barrier disruption induced by cigarette. / Schweitzer, Kelly S.; Hatoum, Hadi; Brown, Mary Beth; Gupta, Mehak; Justice, Matthew J.; Beteck, Besem; van Demark, Mary; Gu, Yuan; Presson, Robert; Hubbard, Walter C.; Petrache, Irina.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 301, No. 6, 12.2011.

Research output: Contribution to journalArticle

Schweitzer, Kelly S. ; Hatoum, Hadi ; Brown, Mary Beth ; Gupta, Mehak ; Justice, Matthew J. ; Beteck, Besem ; van Demark, Mary ; Gu, Yuan ; Presson, Robert ; Hubbard, Walter C. ; Petrache, Irina. / Mechanisms of lung endothelial barrier disruption induced by cigarette. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2011 ; Vol. 301, No. 6.
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AU - Beteck, Besem

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