title: Prevention of neutrophil extravasation by α2-adrenoceptor-mediated endothelial stabilization.
abstract: Adrenergic receptors are expressed on the surface of inflammation-mediating cells, but their potential role in the regulation of the inflammatory response is still poorly understood. The objectives of this work were to study the effects of α2-adrenergic agonists on the inflammatory response in vivo and to determine their mechanism of action. In two mouse models of inflammation, zymosan air pouch and thioglycolate-induced peritonitis models, the i.m. treatment with xylazine or UK14304, two α2-adrenergic agonists, reduced neutrophil migration by 60%. The α2-adrenergic antagonist RX821002 abrogated this effect. In flow cytometry experiments, the basal surface expression of L-selectin and CD11b was modified neither in murine nor in human neutrophils upon α2-agonist treatment. Similar experiments in HUVEC showed that UK14304 prevented the activation-dependent upregulation of ICAM-1. In contrast, UK14304 augmented electrical resistance and reduced macromolecular transport through a confluent HUVEC monolayer. In flow chamber experiments, under postcapillary venule-like flow conditions, the pretreatment of HUVECs, but not neutrophils, with α2-agonists decreased transendothelial migration, without affecting neutrophil rolling. Interestingly, α2-agonists prevented the TNF-α-mediated decrease in expression of the adherens junctional molecules, VE-cadherin, β-catenin, and plakoglobin, and reduced the ICAM-1-mediated phosphorylation of VE-cadherin by immunofluorescence and confocal analysis and Western blot analysis, respectively. These findings indicate that α2-adrenoceptors trigger signals that protect the integrity of endothelial adherens junctions during the inflammatory response, thus pointing at the vascular endothelium as a therapeutic target for the management of inflammatory processes in humans.
authors.affiliation: Departamento de Medicina, Facultad de Medicina, Universidad de La Laguna, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain;
authors.forename: Ada María
authors.initials: AM
authors.lastname: Herrera-García
authors.affiliation: Centro para la Investigación Biomédica de las Islas Canarias, Instituto de Tecnologías Biomedicas, Universidad de La Laguna, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain;
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Domínguez-Luis
authors.affiliation: Servicio de Reumatología, Hospital Universitario de Canarias, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain;
authors.forename: María
authors.initials: M
authors.lastname: Arce-Franco
authors.affiliation: Departamento de Medicina, Facultad de Medicina, Universidad de La Laguna, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain;
authors.forename: Estefanía
authors.initials: E
authors.lastname: Armas-González
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad de La Laguna, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain;
authors.forename: Diego
authors.initials: D
authors.lastname: Álvarez de La Rosa
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de La Laguna, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain;
authors.forename: José David
authors.initials: JD
authors.lastname: Machado
authors.affiliation: Departamento de Medicina, Facultad de Medicina, Universidad de La Laguna, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain;
authors.forename: Martina K
authors.initials: MK
authors.lastname: Pec
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de La Laguna, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: Feria
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Consejo Superior de Investigaciones Cientificas, 28029 Madrid, Spain; and.
authors.forename: Olga
authors.initials: O
authors.lastname: Barreiro
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Consejo Superior de Investigaciones Cientificas, 28029 Madrid, Spain; and Servicio de Inmunología, Hospital Universitario de La Princesa, 28006 Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.affiliation: Departamento de Medicina, Facultad de Medicina, Universidad de La Laguna, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain; Servicio de Reumatología, Hospital Universitario de Canarias, La Cuesta, 38320 San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain; federico.diaz.gonzalez@gmail.com.
authors.forename: Federico
authors.initials: F
authors.lastname: Díaz-González
mesh_terms: D022005:Adherens Junctions / Q000276:immunology*; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000068438:Brimonidine Tartrate; D039481:CD11b Antigen / Q000096:biosynthesis; D015820:Cadherins / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000276:immunology*; D006801:Humans; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D019041:L-Selectin / Q000096:biosynthesis; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000276:immunology*; D010538:Peritonitis / Q000139:chemically induced; D011810:Quinoxalines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000096:biosynthesis / Q000276:immunology*; D013864:Thioglycolates / Q000494:pharmacology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D014991:Xylazine / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology; D051176:beta Catenin / Q000096:biosynthesis; D051185:gamma Catenin / Q000096:biosynthesis; D000099152:Cadherin 5
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000317:Adrenergic alpha-Antagonists; D015703:Antigens, CD; D000068438:Brimonidine Tartrate; D039481:CD11b Antigen; D015820:Cadherins; D019329:Idazoxan; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D014991:Xylazine; D015054:Zymosan; D051176:beta Catenin; D051185:gamma Catenin; D000099152:Cadherin 5; C058525:2-methoxyidazoxan