Intercellular Adhesion Molecule-1–Dependent Neutrophil Adhesion to Endothelial Cells Induces Caveolae-Mediated Pulmonary Vascular Hyperpermeability

We investigated the role of caveolae in the mechanism of increased pulmonary vascular permeability and edema formation induced by the activation of polymorphonuclear neutrophils (PMNs). We observed that the increase in lung vascular permeability induced by the activation of PMNs required caveolin-1,...

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Bibliographic Details
Published in:Circulation research 2008-06, Vol.102 (12), p.e120-e131
Main Authors: Hu, Guochang, Vogel, Stephen M, Schwartz, David E, Malik, Asrar B, Minshall, Richard D
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacology
beta-Cyclodextrins - pharmacology
Capillary Permeability - drug effects
Caveolae - physiology
Caveolin 1 - antagonists & inhibitors
Caveolin 1 - biosynthesis
Caveolin 1 - deficiency
Caveolin 1 - genetics
Caveolin 1 - physiology
Cell Adhesion - physiology
Cells, Cultured - cytology
Cells, Cultured - drug effects
Endocytosis - drug effects
Endocytosis - physiology
Endothelial Cells - cytology
Endothelial Cells - drug effects
Intercellular Adhesion Molecule-1 - physiology
Lung - blood supply
Mice
Mice, Knockout
Neutrophils - drug effects
Neutrophils - physiology
Phosphorylation - drug effects
Protein Processing, Post-Translational - drug effects
Proto-Oncogene Proteins pp60(c-src) - physiology
Pulmonary Edema - physiopathology
Rats
Rats, Sprague-Dawley
RNA, Small Interfering - pharmacology
Serum Albumin - pharmacokinetics
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Summary:We investigated the role of caveolae in the mechanism of increased pulmonary vascular permeability and edema formation induced by the activation of polymorphonuclear neutrophils (PMNs). We observed that the increase in lung vascular permeability induced by the activation of PMNs required caveolin-1, the caveolae scaffold protein. The permeability increase induced by PMN activation was blocked in caveolin-1 knockout mice and by suppressing caveolin-1 expression in rats. The response was also dependent on Src phosphorylation of caveolin-1 known to activate caveolae-mediated endocytosis in endothelial cells. To address the role of PMN interaction with endothelial cells, we used an intercellular adhesion molecule (ICAM)-1 blocking monoclonal antibody. Preventing the ICAM-1–mediated PMN binding to endothelial cells abrogated Src phosphorylation of caveolin-1, as well as the increase in endothelial permeability. Direct ICAM-1 activation by crosslinking recapitulated these responses, suggesting that ICAM-1 activates caveolin-1 signaling responsible for caveolae-mediated endothelial hyperpermeability. Our results provide support for the novel concept that a large component of pulmonary vascular hyperpermeability induced by activation of PMNs adherent to the vessel wall is dependent on signaling via caveolin-1 and increased caveolae-mediated transcytosis. Thus, it is important to consider the role of the transendothelial vesicular permeability pathway that contributes to edema formation in developing therapeutic interventions against PMN-mediated inflammatory diseases such as acute lung injury.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.107.167486