Rh. Fabian et Ta. Kent, Superoxide anion production during reperfusion is reduced by an antineutrophil antibody after prolonged cerebral ischemia, FREE RAD B, 26(3-4), 1999, pp. 355-361
Neutrophils may be involved in the pathophysiology of reperfusion injury fo
llowing cerebral ischemia. One potential mechanism of reperfusion injury by
neutrophils is through production of the superoxide anion. We hypothesized
that, due to progressive endothelial damage during ischemia, neutrophil ac
tivation would be more prominent after longer periods of ischemia prior to
reperfusion. Thus, neutrophils would contribute more to pathological proces
ses such as superoxide anion formation after longer than after shorter peri
ods of ischemia. A reversible middle cerebral artery occlusion model in rat
s was employed and superoxide anion concentration was measured with a cytoc
hrome c coated electrode placed on the cortical penumbral region. Occlusion
times were varied from 60 min to 2 h, and neutrophils were inhibited with
an antiCD18 antibody administered prior to occlusion. Neutrophil accumulati
on and reduction with antibody treatment was confirmed immunohistochemicall
y. Superoxide anion (O-2(.-)) concentration was detected during the hours f
ollowing 60 min of occlusion, and increased further with 2 h of occlusion.
Treatment with the antiCD18 antibody had no effect on O-2(.-) concentration
during reperfusion in the 60-90 min occlusion groups, but O-2(.-) concentr
ation was significantly lower in the antiCD18 antibody treated group than i
n the control group during reperfusion after 120 min of ischemia. The antib
ody also reduced cortical neutrophil accumulation in the 120 min ischemia g
roup. These results indicate for the first time that superoxide production
by neutrophils becomes more important with longer periods of ischemia, and
other quantitatively less important sources of superoxide predominate with
shorter periods of ischemia. This phenomenon may explain some of the variat
ion seen between different models of ischemia with different durations of i
schemia when targeting reactive oxygen species, and supports an approach to
combination therapy to extend the therapeutic window and reduce the delete
rious effects of reperfusion. (C) 1998 Elsevier Science Inc.