Fa. Delano et al., ATTENUATION OF OXYGEN-FREE RADICAL FORMATION AND TISSUE-INJURY DURINGEXPERIMENTAL INFLAMMATION BY P-SELECTIN BLOCKADE, Microcirculation, 4(3), 1997, pp. 349-357
Objective: Neutrophilic leukocyte rolling on postcapillary endothelium
requires membrane interaction between SLe(x)-containing ligands on ne
utrophils and P-selectin on endothelial cells. The current sequence of
studies was performed to explore the hypothesis that the leukocyte-en
dothelial rolling interaction not only precedes leukocyte migration bu
t also is accompanied by oxygen free radical production and interstiti
al cell death in the rat mesentery. Methods: The ratio of leukocyte ro
lling velocity on the endothelium of postcapillary venules and centerl
ine red cell velocity was determined after topical application of plat
elet activating factor (PAF; 10(-8) mol/L). Superoxide formation was d
etermined by an in situ nitroblue tetrazolium reduction to dark blue f
ormazan crystals in the in situ mesentery preparation, and cell death
was detected by nuclear staining with propidium iodide. Results: Leuko
cyte rolling and subsequent adhesion was inhibited with a monoclonal a
ntibody against P-selectin, PB1.3. Superoxide formation, as well as pa
renchymal cell death, was significantly enhanced in the mesentery afte
r stimulation with platelet activating factor, and both could be signi
ficantly attenuated by reduction of die rolling leukocyte-endothelial
interaction with PB1.3. Conclusions: These results provide direct evid
ence that the interaction of leukocytes and endothelium followed by mi
gration of leukocytes into the interstitium is accompanied by entrance
d oxidative stress and parenchymal cell death. Early interruption of t
he interaction provides significant protection even in the presence of
a proinflammatory stimulus.