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This Article Full Text Full Text (PDF) All Versions of this Article: 291/4/L764    most recent 00502.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Orrington-Myers, J. Articles by Malik, A. B. Search for Related Content PubMed PubMed Citation Articles by Orrington-Myers, J. Articles by Malik, A. B.

Regulation of lung neutrophil recruitment by VE-cadherin

Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois

Submitted 28 November 2005 ; accepted in final form 6 May 2006

Lung inflammatory disease is characterized by increased polymorphonuclear leukocyte (PMN) infiltration and vascular permeability. PMN infiltration into tissue involves signaling between endothelial cells and migrating PMNs, which leads to alterations in the organization of adherens junctions (AJs). We addressed the possible role of the protein constituents of AJs, endothelium-specific vascular-endothelial (VE)-cadherin, in the migration of PMNs. Studies were made using VE-cadherin mutant constructs lacking the extracellular domain (EXD) or, additionally, lacking the COOH-terminus -catenin-binding domain (EXD). Either construct was transduced in pulmonary microvessel endothelia of mice using cationic liposome-encapuslated cDNA constructs injected intravenously. Optimal expression of constructs was seen by Western blot analysis within 24 h. Vessel wall liquid permeability measured as the lung microvessel capillary filtration coefficient increased threefold in EXD-transduced lungs, indicating patency of interendothelial junctions, whereas the control EXD construct was ineffective. To study lung tissue PMN recruitment, we challenged mice intraperitoneally with LPS (3 mg/kg) for 6 h and measured PMN numbers by bronchoalveolar lavage and their accumulation morphometrically in lung tissue. EXD expression markedly reduced the PMN sequestration and migration seen in nontransfected (control wild type) or EXD-transfected (negative control) mice challenged with LPS. In addition, EXD transfection suppressed LPS-induced activation of NF-B and consequent ICAM-1 expression. These results suggest that disassembly of VE-cadherin junctions serves as a negative signal for limiting transendothelial PMN migration secondary to decreased ICAM-1 expression in the mouse model of LPS-induced sepsis.

vascular endothelial cadherin; intercellular adhesion molecule-1; polymorphonuclear leukocyte adhesion; vascular endothelial-cadherin mutants