Leukocyte rolling and firm adhesion in the microvasculature : functional significance for leukocyte recruitment in inflammation
Author: Xie, Xun
Date: 1998-01-16
Location: Föreläsningssalen, Doktorsringen 6A
Time: 9.00
Abstract
Leukocyte recruitment to tissues is a key component in the inflammatory
process.In order for circulating leukocytes to extravasate, they need to
interact with vascularendothelium in several sequential steps. Slow
rolling along the endothelial liningis the initial step in this sequence
of events, followed by firm adhesion to endotheliumand subsequent
transmigration across the vessel wall. These interactions are governedby
adhesion molecules expressed on the surface of leukocytes and endothelial
cells,i.e. Ieukocyte rolling is mediated predominantly by adhesion
molecules of the selectinfamily whereas firm adhesion is mediated by
integrin molecules. This intravital microscopicstudy aimed at
investigating leukocyte/endothelium interactions in inflammation
withfocus on the functional significance of leukocyte rolling for
subsequent steps inthe leukocyte extravasation process.
The quantitative relationship between chemoattractant-induced leukocyte
firm adhesionand the preceding rolling interaction was investigated in
rat mesenteric venules.Systemic treatment with fucoidin, a sulfated
polysaccharide which interferes withselectin-receptor function, resulted
in a dose-dependent inhibition of leukocyterolling. Secondary to this
effect, chemoattractant-induced firm leukocyte adhesionwas reduced in
proportion to the decrease in leukocyte rolling. The data demonstratea
close relationship between the extent of leukocyte rolling and the firm
adhesiveresponse, and that the initial rolling interaction is a necessary
precondition forsubsequent steps in the extravasation process. Further
studies in the rabbit showedthat inhibition of leukocyte rolling with
fucoidin profoundly reduced neutrophilinfiltration in inflammatory skin
lesions, and leukocyte accumulation in the cerebrospinalfluid in an
experimental meningitis model, thus illustrating a therapeutic
potentialof inhibiting leukocyte rolling (e.g. with carbohydrate
molecules) in inflammatorydisorders.
Heparin and related glycans may, similarly to fucoidin, interfere with
leukocyte/endotheliuminteractions. It was demonstrated that heparin has
inhibitory actions on both leukocyterolling and chemoattractant-induced
firm adhesion, and that it may increase localblood flow. Attenuation of
the firm adhesive response at low concentrations of heparincould be
ascribed mainly to inhibition of selectin-mediated leukocyte rolling,
whereasat high concentrations of heparin a direct effect on
integrin-mediated firm adhesionwas indicated. Because of interference
with several microvascular functions, strictdose-dependent responses to
heparin treatment were not found, illustrating a complexinterplay between
local blood flow, leukocyte rolling, and firm adhesion as determinantsof
leukocyte recruitment to tissues in inflammation.
These interrelationships and the influence of microhemodynamics on
leukocyte/endotheliuminteractions were characterized in more detail. The
rolling leukocyte flux was directlyproportional to the total leukocyte
flux, and to the venular blood flow. Consequently,the rolling/total
leukocyte flux fraction did not vary with blood flow and showedno
correlation to wall shear rate. Firm leukocyte adhesion evoked by
chemoattractantstimulation was quantitatively related to the rolling
leukocyte flux, and hence tothe venular blood flow, while there was no
correlation to the wall shear rate. Thedata indicate that leukocyte
adhesion to the venular endothelium, because of itsdependence on the
preceding rolling interaction, is proportional to the microvesselblood
flow, which emphasizes the importance of tissue hyperemia for leukocyte
recruitmentin inflammation.
Analysis of the rolling characteristics of polymorphonuclear (PMN) and
mononuclear(MN) leukocytes indicated that the great majority of PMN
leukocytes passing in venulesof the rat mesentery rolled along the
endothelial lining, whereas MN leukocytes wererolling only to a small
extent under the same basal conditions. In cytokine-activatedtissue, on
the other hand, MN leukocyte rolling was substantially increased.
Differencesbetween the leukocyte subpopulations in their binding
interaction with the endothelialselectins and a dependence of MN
leukocyte rolling on a4 integrins were suggestedto govern the discrete
rolling characteristics, and are likely to contribute to thetemporal
selectivity in the recruitment of leukocyte subclasses to inflamed
tissuesites.
Keywords: adhesion molecules, blood flow, chemoattractants, endothelium,
flowcytometry, fucoidin, heparin, inflammation, integrins, intravital
microscopy, leukocyteadhesion, leukocyte extravasation, leukocyte
rolling, meningitis, mesentery, microcirculation,rabbit, rat, selectins
ISBN 91-628-2830-4
Issue date: 1997-12-26
Publication year: 1998
ISBN: 91-628-2830-4
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