Abstract
The selectin-mediated rolling of leukocytes along the endothelial cells is a prerequisite step followed by firm adhesion and extravasation into the inflamed tissue. This initial contact can be suppressed by sulphated polysaccharides. We have studied the effect of sulphated polysaccharides on the ultimate polymorphonuclear leukocyte (PMN) recruitment and plasma leakage in rabbit skin in response to intradermal injection of various inflammatory mediators. PMN infiltration evoked by various PMN chemoattractants (FMLP, C5a desArg, LTB4 and IL-8) was significantly inhibited after intravenous injection of dextran sulphate (25 mg/kg), heparin (2 × 90 mg/kg) or fucoidan (1 mg/kg). PMN-dependent plasma leakage was equally well reduced by the different sulphated polymers. Vascular permeability induced by histamine or thrombin acting via a PMN-independent mechanism was not reduced. Fucoidan was the only polysaccharide able to suppress IL-1-induced PMN infiltration for 60–70%. Local administration of dextran sulphate had no effect on PMN-dependent plasma leakage. Differential inhibition of PMN recruitment was determined after injection of dextran sulphate or fucoidan depending on the type of insult. Therefore, these results suggest that different adhesion pathways are utilized during PMN recruitment in vivo in response to chemoattractants and IL-1.
Highlights
An inflammatory reaction is characterized by leukocyte emigration and plasma protein leakage from the blood stream into the extravascular injured tissue
Leukocyte recruitment is designed as a multistep process in which several types of cell adhesion molecules are involved.1’2 The initial contact of leukocytes with postcapillary endothelial cells, described as rolling, is mediated by the selectin family of adhesion molecules.3’4 The subsequent firm adhesion and transmigration through the endothelial cell lining into the inflamed tissue is mediated by leukocyte fi2-integrins (CD 11/CD 18) and endothelial immunoglobulin-like molecules (ICAM-1 and PECAM-1).[5,6,7]
Intravenous injection of dextran sulphate (25 mg/kg, 30 rain before the start of the experiment), completely abolished PMN infiltration and plasma extravasation in response to the PMN chemoattractants. This concentration of dextran sulphate had been shown to inhibit leukocyte rolling in rabbit mesenteric venules for more than 90%
Summary
An inflammatory reaction (e.g. adult respiratory distress syndrome, ischaemic reperfusion injury or arthritis) is characterized by leukocyte emigration and plasma protein leakage from the blood stream into the extravascular injured tissue. Leukocyte recruitment is designed as a multistep process in which several types of cell adhesion molecules are involved.1’2 The initial contact of leukocytes with postcapillary endothelial cells, described as rolling, is mediated by the selectin family of adhesion molecules.3’4 The subsequent firm adhesion and transmigration through the endothelial cell lining into the inflamed tissue is mediated by leukocyte fi2-integrins (CD 11/CD 18) and endothelial immunoglobulin-like molecules (ICAM-1 and PECAM-1).[5,6,7]. The selectin family consists of three closely related cell surface molecules: L-selectin. Originally described as a lymphocyte homing receptor (MEL-14)[8] is constitutively present on PMNs, monocytes and most of the lymphocytes. PMN activation results in a rapid removal of L-selectin from the cell surface (shedding).[9] P-selectin normally exists preformed in a-granules of platelets and in Weibel-
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