Regulation of lung neutrophil recruitment by VE-cadherin

Regulation of lung neutrophil recruitment by VE-cadherin. Am J Physiol Lung Cell Mol Physiol 291: L764-L771, 2006. First published June 16, 2006; doi: 10.1152/ajplung. 00502.2005.-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 (Delta EXD) or, additionally, lacking the COOH-terminus beta-catenin-binding domain (Delta EXD Delta beta). 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 Delta EXD-transduced lungs, indicating patency of interendothelial junctions, whereas the control Delta EXD Delta beta 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. Delta EXD expression markedly reduced the PMN sequestration and migration seen in nontransfected (control wild type) or Delta EXD Delta beta-transfected ( negative control) mice challenged with LPS. In addition, Delta EXD transfection suppressed LPS-induced activation of NF-kappa 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.