Platelets modulate ischemia/reperfusion-induced leukocyte recruitment in the mesenteric circulation

2001 ◽  
Vol 281 (6) ◽  
pp. G1432-G1439 ◽  
Author(s):  
James W. Salter ◽  
Christian F. Krieglstein ◽  
Andrew C. Issekutz ◽  
D. Neil Granger
Keyword(s):  
Monoclonal Antibody ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Ischemia Reperfusion ◽  
Leukocyte Recruitment ◽  
Leukocyte Adherence ◽  
Neutrophil Accumulation ◽  
Treatment Groups ◽  
Vascular Beds ◽  
Endothelial Cell Adhesion

P-selectin-dependent leukocyte-endothelial cell adhesion has been implicated in the pathogenesis of ischemia/reperfusion (I/R) injury in several vascular beds, including the gut. Because platelet-endothelial (P/E) cell adhesion also occurs in postischemic venules, the possibility exists that the expression of P-selectin on the surface of platelets that are adherent to venular endothelial cells may mediate the leukocyte recruitment elicited by I/R. P-selectin expression [dual radiolabeled monoclonal antibody (MAb) technique] and neutrophil accumulation [myeloperoxidase (MPO) activity] were measured in the postischemic small intestine of untreated rats and rats treated with either antiplatelet serum (APS) or MAbs directed against either P-selectin, GPIIb/IIIa, or fibrinogen. The increases in P-selectin expression and tissue MPO normally elicited by I/R were significantly attenuated in the different treatment groups, suggesting that I/R-induced neutrophil recruitment is a platelet-dependent, P-selectin-mediated process. Intravital microscopy was then employed to examine this process relative to leukocyte-endothelial cell adhesion in postischemic rat mesenteric venules. The recruitment of adherent and emigrated leukocytes after I/R was attenuated by pretreatment with a MAb against, either P-selectin, GPIIb/IIIa, or fibrinogen, as well as an Arg-Gly-Asp peptide. Whereas thrombocytopenia greatly blunted leukocyte emigration, it did not alter the leukocyte adherence response to I/R. These findings suggest that platelet-associated P-selectin contributes to the accumulation of leukocytes in postischemic tissue via a mechanism that alters transendothelial leukocyte migration.

scholarly journals Anti-inflammatory drugs and endothelial cell adhesion molecule expression in murine vascular beds

Gut ◽  
1999 ◽  
Vol 44 (2) ◽  
pp. 186-195 ◽  
Author(s):  
N Mori ◽  
Y Horie ◽  
M E Gerritsen ◽  
D C Anderson ◽  
D N Granger
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Adhesion Molecules ◽  
Adhesion Molecule ◽  
Distal Colon ◽  
Intercellular Adhesion Molecule ◽  
Aminosalicylic Acid ◽  
Antibody Technique ◽  
Vascular Beds ◽  
Endothelial Cell Adhesion

BackgroundInflammatory bowel diseases (IBD) are characterised by an intense infiltration of leucocytes that is mediated by adhesion molecules expressed on the surface of activated endothelial cells.AimsTo determine whether drugs used in the treatment of IBD, specifically dexamethasone (DEX), 5-aminosalicylic acid (5-ASA), methotrexate (MTX), and 6-mercaptopurine (6-MP), alter the expression of endothelial cell adhesion molecules (ECAMs).MethodsThe expression of P-selectin, E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular CAM 1 (VCAM-1) in different vascular beds of C57Bl/6J mice was measured using the dual radiolabelled monoclonal antibody technique.ResultsLipopolysaccharide (LPS) elicited a profound increase in the expression of all ECAMs in the mesentery, small intestine, caecum, and distal colon. The LPS induced increase in CAM expression was not significantly affected by prior treatment with either MTX or 6-MP. However, pretreatment with either DEX or 5-ASA significantly attenuated LPS induced increases in expression of P- and E-selectin, and VCAM-1 in the majority of tissues evaluated. DEX also blunted the LPS induced increase in ICAM-1 expression in the caecum and distal colon. DEX, but not 5-ASA, largely abolished the rise in plasma tumour necrosis factor α elicited by LPS.ConclusionsThese findings suggest that DEX and 5-ASA may exert their beneficial therapeutic action in IBD, at least in part, by inhibiting the expression of ECAMs which mediate leucocyte adhesion and transmigration in the microvasculature.

scholarly journals Solid-phase von Willebrand factor contains a conformationally active RGD motif that mediates endothelial cell adhesion through the alpha v beta 3 receptor

Blood ◽  
1993 ◽  
Vol 82 (12) ◽  
pp. 3622-3630 ◽  
Author(s):  
C Denis ◽  
JA Williams ◽  
X Lu ◽  
D Meyer ◽  
D Baruch
Keyword(s):  
Monoclonal Antibody ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Von Willebrand Factor ◽  
Solid Phase ◽  
Rgd Sequence ◽  
Alpha V Beta 3 ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Endothelial Cell Adhesion

Abstract The interaction of von Willebrand factor (vWF) with the alpha v beta 3 integrin of human umbilical vein endothelial cells is dependent on the RGD sequence present at residues 1744–1746 of the mature vWF subunit. We compared vWF and its two dimeric fragments, SpIII (residues 1–1365) and SpII (residues 1366–2050), as adhesion substrates. Solid-phase vWF and SpII supported endothelial cell adhesion, whereas SpIII, which contains the glycoprotein (GP) Ib binding domain, did not. Soluble SpII inhibited adhesion to immobilized ligands, whereas soluble vWF did not, suggesting that exposure of the cell attachment domain involves a conformational modification of vWF. Dendroaspin and albolabrin, two RGD- containing peptides of the disintegrin family, were potent inhibitors of cell adhesion to vWF (IC50 approximately 15 nmol/L). Complete inhibition of endothelial cell adhesion to vWF was obtained in the presence of F(ab')2 of monoclonal antibody 9 to vWF, which blocks vWF binding to platelet GPIIb/IIIa. In contrast, monoclonal antibody 713 to vWF, which blocks its binding to platelet GPIb, did not inhibit cell adhesion to vWF. These results indicate that endothelial cell adhesion to vWF is mediated by an RGD-dependent interaction with alpha v beta 3, but does not seem to involve a GPIb-like receptor, and show the importance of the conformation of the RGD sequence.

Pentamidine Is a Specific, Non-Peptide, GPIIb/llla Antagonist

1996 ◽  
Vol 75 (03) ◽  
pp. 503-509 ◽  
Author(s):  
Dermot Cox ◽  
Toshiaki Aoki ◽  
Jiro Seki ◽  
Yukio Motoyama ◽  
Keizo Yoshida
Keyword(s):  
Monoclonal Antibody ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
Intracellular Ph ◽  
Platelet Adhesion ◽  
Adhesion Assay ◽  
Agonist Peptide ◽  
A Cell ◽  
Granule Release ◽  
Endothelial Cell Adhesion

SummaryPentamidine was previously shown to act on glycoprotein (GP) Ilb/IIIa (Cox et al., Thromb Haemost 1992; 68: 731). In this paper we study the effect of pentamidine on other RGD-dependent receptors. In a cell adhesion assay, pentamidine was 500 times more potent than RGDS at inhibiting platelet adhesion to fibrinogen. While RGDS inhibited platelet adhesion to fibronectin, endothelial cell adhesion to vitronectin or fibronectin, 293 cell adhesion to vitronectin, IMR 32 cell adhesion to fibronectin and C32 cell adhesion to vitronectin; pentamidine failed to inhibit these interactions at doses as high as 1 mM. Resting platelets fixed in the presence of 1 mM RGDS had increased binding of fibrinogen, i.e., RGDS activated GPIMIIa, while pentamidine at 100 ΜM had no effect. Similarly, RGDS induced the binding of an anti-LIBS monoclonal antibody, while pentamidine had no effect. Pentamidine partially, but significantly, inhibited lysosome and a-granule release induced by the thrombin agonist peptide, while RGDS had no effect. Neither pentamidine nor RGDS affected ADP-induced Ca2+ influx. Pentamidine had no effect on ADP-induced intracellular pH changes while RGDS prevented the pH from returning to normal. Thus, pentamidine is a non-peptide GPIIb/IIIa antagonist that is non-activating and is specific for GPIIb/IIIa.

Loss of Endothelial Surface Expression of E-Selectin in a Patient With Recurrent Infections

Blood ◽  
1999 ◽  
Vol 94 (3) ◽  
pp. 884-894 ◽  
Author(s):  
Horace M. DeLisser ◽  
Melpo Christofidou-Solomidou ◽  
Jing Sun ◽  
Marian T. Nakada ◽  
Kathleen E. Sullivan
Keyword(s):  
Cell Adhesion ◽  
Endothelial Cell ◽  
Adhesion Molecules ◽  
Cell Adhesion Molecules ◽  
Leukocyte Adhesion ◽  
Leukocyte Recruitment ◽  
Recurrent Infections ◽  
Sialyl Lewisx ◽  
Leukocyte Adhesion Deficiency ◽  
Endothelial Cell Adhesion

Neutrophil accumulation at sites of inflammation is mediated by specific groups of cell adhesion molecules including the β2 (CD18) integrins on leukocytes and the selectins (P- and E-selectin on the endothelium and L-selectin on the leukocyte). This is supported by studies of patients with leukocyte adhesion deficiency syndromes whose leukocytes are genetically deficient in the expression of β2 integrins or selectin carbohydrate ligands (eg, sialyl-Lewisx). However, inherited deficiency or dysfunction of endothelial cell adhesion molecules involved in leukocyte recruitment has not been previously described. In this report we describe a child with recurrent infections and clinical evidence of impaired pus formation reminiscent of a leukocyte adhesion deficiency syndrome, but whose neutrophils were functionally normal and expressed normal levels of CD18, L-selectin, and sialyl-Lewisx. In contrast, immunohistochemical staining of inflamed tissue from the patient showed the absence of E-selectin from the endothelium, although E-selectin mRNA was present. However, E-selectin protein was expressed as significantly elevated levels of circulating soluble E-selectin were detected, the molecular size of which was consistent with a proteolytically cleaved form of E-selectin. Gene sequencing failed to show evidence of a secreted mutant variant. These data represent, to our knowledge, the first description of a potentially inherited dysfunction of an endothelial cell adhesion molecule involved in leukocyte recruitment and provide additional human evidence of the importance of endothelial selectins in the inflammatory response.

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