FIBRINOGEN MEDIATES LEUKOCYTE-ENDOTHELIUM BRIDGING IN-VIVO AT LOW SHEAR FORCES

In addition to preserving hemostasis, fibrinogen assembly on leukocyte s mediates inflammatory responses and may aberrantly contribute to vas cular injury, In this study, we used real-time intravital video micros copy in exposed rabbit mesentery to investigate the potential role of fibrinogen on leukocyte adherence mechanisms, in vivo. At physiologic concentrations of 0.15 to 0.5 mg/ml, human fibrinogen dose-dependently enhanced by threefold to fivefold the adhesion of chemoattractant-sti mulated monocytic HL-60 cells to rabbit mesenteric endothelium, by act ing as a bridging molecule between the two cell types. Fibrinogen-depe ndent intercellular bridging occurred in venules, but not in arteriole s or capillaries (1), was optimal at reduced flow shear forces (range: 0.77 to 2.79 dyne/cm(2)) (2), and produced a firm attachment of monoc ytic cells to endothelium, rather than transient rolling (3). Consiste nt with this model, rabbit fibrinogen failed to support human leukocyt e adhesion, while human fibrinogen enhanced monocytic cell attachment to rabbit endothelial cells in vitro, in a reaction indistinguishable from that observed with human endothelium. Antagonists of the recently described association of fibrinogen with intercellular adhesion molec ule-1 (ICAM-1), including monoclonal antibodies (MoAbs) LB-2 or 2D5, o r the fibrinogen gamma 3 peptide gamma Asn(117)-Ala(133), blocked fibr inogen-dependent leukocyte-endothelium interaction in vitro or in vivo , respectively, while a control nonbinding antibody or the fibrinogen L10 peptide gamma Leu(402)-Val(411) were ineffective. These data sugge st that simultaneous assembly of fibrinogen on leukocytes and endothel ial ICAM-1 provides a pathway of intercellular adhesion which may act in concert with beta(2) integrins to stabilize firm leukocyte attachme nt to endothelium, in vivo. Given the recognized role of fibrinogen as a major risk factor for atherosclerosis, this mechanism may directly contribute to thrombus formation and endothelial cell damage in vascul ar diseases. (C) 1996 by The American Society of Hematology.