Lung inflammatory disease is characterized by increased polymorphonuclear leukocyte (PMN) inflitration and vascular permeability. PMN infiltration into tissues involves signaling between endothelial cells and migrating PMN's, which leads to alterations in the organization of adherens junctions (AJs). We addressed the possible role of the protein constituents of AJs, the endothelial-specific VE (vascular-endothelial)-cadherin, in the migration of PMNs. Studies were made using VE-cadherin mutant constructs lacking the extracellular domain (EXD) or additionally COOH-terminus B-catenin-binding domain (EXDB). Either construct was transduced in pulmonary microvessel endothelia of mice using cationic liposome-encapsulated cDNA constructs injected i.v. Optimal expression of constructs was seen by Western blotting within 24 hr. Vessel wall liquid permeability measured as the lung microvessel filtration coefficient (K_f,c) increased 3-fold in EXD-transduced lungs indicating patency of interendothelial junctions, whereas the control EXDB construct was ineffective. To study lung tissue PMN recruitment, we challenged mice i.p. with LPS (3 mg/kg) for 6 hrs and measured PMN numbers by BAL and their accumulation morphometrically in lung tissue. EXD expression markedly reduced PMN sequestration and migration seen in nontransfected (control wild type) or EXDB-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 migration secondary to decreased ICAM-1 expression in the mouse-model of LPS-induced sepsis.