title: Regulation of lung neutrophil recruitment by VE-cadherin.
abstract: 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 (DeltaEXD) or, additionally, lacking the COOH-terminus beta-catenin-binding domain (DeltaEXDDeltabeta). 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 DeltaEXD-transduced lungs, indicating patency of interendothelial junctions, whereas the control DeltaEXDDeltabeta 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. DeltaEXD expression markedly reduced the PMN sequestration and migration seen in nontransfected (control wild type) or DeltaEXDDeltabeta-transfected (negative control) mice challenged with LPS. In addition, DeltaEXD transfection suppressed LPS-induced activation of NF-kappaB 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.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Janie
authors.initials: J
authors.lastname: Orrington-Myers
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Gao
authors.forename: Panos
authors.initials: P
authors.lastname: Kouklis
authors.forename: Michael
authors.initials: M
authors.lastname: Broman
authors.forename: Arshad
authors.initials: A
authors.lastname: Rahman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Vogel
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D022005:Adherens Junctions / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism*; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008833:Microcirculation; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000502:physiology*; D017434:Protein Structure, Tertiary; D014162:Transfection; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D018799:Intercellular Adhesion Molecule-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000099152:Cadherin 5