title: Staphylococcus aureus alpha toxin mediates polymorphonuclear leukocyte-induced vasocontraction and endothelial dysfunction.
abstract: The effect of Staphylococcus aureus alpha toxin (alpha-toxin) on selectin-mediated neutrophil adhesion was investigated in polymorphonuclear leukocyte- (PMN) induced vasocontraction and endothelial dysfunction. Adherence of human PMNs to rat aortic endothelium increased significantly following stimulation of the endothelium with alpha-toxin (0.1, 0.5, and 1 microg/mL). This effect could be significantly attenuated by monoclonal antibodies directed against P-selectin or fucoidin, a carbohydrate known to block selectins. Unstimulated human PMNs (10(6)cells/mL) were added to organ chambers containing rat aortic rings stimulated with alpha-toxin (0.5 microg/mL). PMNs elicited a significant vasocontraction in alpha-toxin-stimulated, but not in control aortic, rings (142+/-12 mg versus 12+/-4 mg, P < 0.05). This PMN-induced vasocontraction was virtually blunted by pretreatment with MAb directed against P-selectin or fucoidin (P < 0.05). Endothelial function as assessed by endothelium-dependent vasorelaxation to acetylcholine was substantially inhibited after induction of PMN-induced vasocontraction in alpha-toxin-stimulated aortic rings. This endothelial dysfunction was reduced by P-selectin MAb or fucoidin. In contrast, endothelium-independent relaxation to sodium nitrite was not altered by PMN incubation, indicating that vascular smooth muscle function was unaffected. Thus, PMN-endothelial interaction following S. aureus a-toxin activation of the vascular endothelium is at least, in part, mediated by selectins. As a consequence, PMN-induced vasocontraction and endothelial dysfunction occur. Such mechanisms may be involved in microcirculation abnormalities encountered in sepsis or septic shock due to S. aureus infection.
authors.affiliation: Department of Medicine, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
authors.forename: Ulf
authors.initials: U
authors.lastname: Sibelius
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
authors.forename: Ute
authors.initials: U
authors.lastname: Buerke
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Meyer
authors.forename: Harald
authors.initials: H
authors.lastname: Darius
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001381:Azepines / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006460:Hemolysin Proteins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D013917:Thrombin / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D001381:Azepines; D001427:Bacterial Toxins; D005343:Fibrinolytic Agents; D006460:Hemolysin Proteins; D014230:Triazoles; C021091:staphylococcal alpha-toxin; C052518:WEB 2086; D013917:Thrombin