The effects of heparin on the adhesion of human peripheral blood mononuclear cells to human stimulated umbilical vein endothelial cells

Abstract

1 The e ects of unfractionated heparin (UH) and a selectively O-desulphated derivative of heparin (ODSH), lacking anticoagulant activity, on the adhesion of human peripheral blood mononuclear cells (HPBMNC) to human stimulated umbilical vein endothelial cells (HUVECs), were investigated. 2 For comparison, the e ects of poly-L-glutamic acid (PGA), a large polyanionic molecule without sulphate groups and two di erent molecular weight sulphated dextrans (DS 5 k and DS 10 k) were studied. 3 UH (50 ± 1000 u ml 71 ) signi®cantly (P50.05) inhibited the adhesion of HPBMNC to HUVECs, stimulated with IL-1b (100 u ml 71 ), TNF-a (1000 u ml 71 ) or LPS (100 mg ml 71 ), when the drugs were added together with stimuli to HUVECs and coincubated for 6 h. Such e ects on adhesion occurred with limited in¯uence on expression of relevant endothelial adhesion molecules (ICAM-1 and VCAM-1). 4 UH (100 ± 1000 u ml 71 ), when added to prestimulated HUVECs, signi®cantly (P50.05) increased adhesion of mononuclear cells to endothelium at the higher concentrations tested, without any e ect on adhesion molecule expression. In contrast, the opposite e ect was observed when human polymorphonuclear leucocyte adhesion was examined, under the same experimental conditions, suggesting that the observed potentiation of HPBMNC adhesion is cell speci®c. 5 The e ects of UH on HPBMNC adhesion were shared by the non-anticoagulant ODSH (600 ± 6000 mg ml 71 ) but not by sulphated dextrans or PGA (300 ± 6000 mg ml 71 ). 6 Heparin a ects the adhesion of HPBMNC to stimulated endothelium, in both an inhibitory and potentiating manner, e ects which are unrelated to its anticoagulant activity and not solely dependent on molecular charge characteristics.

Heparanase induces inflammatory cell recruitment in vivo by promoting adhesion to vascular endothelium

“…Leukocyte-endothelial adhesion was examined using an assay described previously (15,31). Peripheral venous blood was drawn from healthy volunteers into citrated tubes.…”

Pharmacology of Heparin and Related Drugs

“…Heparin has been shown to inhibit the adhesion of leukocytes to endothelium both in vitro (Bazzoni et al, 1993;Silvestro et al, 1994;Lever et al, 2000;Smailbegovic et al, 2001) and in vivo (Ley et al, 1991;Tangelder and Arfors, 1991;Nelson et al, 1993;Xie et al, 1997;Salas et al, 2000;Johnson et al, 2004;Lever et al, 2010). Furthermore, the ultimate accumulation of cells in inflamed tissue sites, in response to both allergic (Sasaki et al, 1993;Seeds et al, 1995;Seeds and Page, 2001;Vancheri et al, 2001) and nonallergic (Nelson et al, 1993;Teixeira and Hellewell, 1993;Yanaka and Nose, 1996;Johnson et al, 2004;Lever et al, 2010) stimuli, is inhibited by heparin.…”

Proteoglycan Involvement in Inflammatory Diseases. New Developments in GAG-Based Therapies

“…Heparin has been shown to interfere with the selectinligand interaction which is the first step of leukocyte recruitment from the vasculature to a site of inflammation [81][82][83][84][85]168]. The sulfation level of heparin seems to correlate with the inhibition of leukocyte recruitment since the use of lower-sulfated derivatives (such as N-desulfated heparin or 2-O-desulfated heparins) were less efficient than heparin to block leukocyte recruitment and adhesion [82].…”

“…The recruitment of leukocytes into tissue is regulated by a sequence of interactions between the circulating leukocytes and the endothelium, and is mediated by adhesion receptors, which include integrins, selectins and cell surface PG [78][79][80]. Some findings suggest a direct role of HSPG and heparin in the adhesion of leukocytes to vascular endothelium [81][82][83][84][85]. Leukocyte adhesion is partially mediated by binding of Mac-1 [86] or L-selectin [78] to HSPG from endothelial cells.…”

“…Moreover, soluble heparin can inhibit Mac-1-dependent leukocyte adhesion on endothelial cells and can attenuate inflammatory and proliferative stimuli associated with the emigration of leukocytes [78]. There are various examples of how HS/heparin are able to inhibit the recruitment of leukocytes to various tissues such as lung, skin and gut [81][82][83][84][87][88][89]. Non-anticoagulant derivatives of heparin have been shown to mimic heparin and prevent leucocytes recruitment [81,82].…”