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Prevention
of Cerebral Edema and Infarct in Cerebral Reperfusion Injury by an Antibody
to Interleukin-8 |
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Tetsuya Matsumoto,
Kiyonobu Ikeda, Naofumi Mukaida, Akihisa Harada, Yoshihiro Matsumoto, Junkoh
Yamashita, and Kouji Matsushima |
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Department
of Neurosurgery (TM, KI, JY), School of Medicine, and Department of Pharmacology
(TM, NM, AH, KM), Cancer Research Institute, Kanazawa University, Kanazawa;
Fuji Gotemba Research Labs (YM), Chugai Pharmaceutical Company Ltd., Gotemba;
and Department of Molecular Preventive Medicine (KM), School of Medicine,
University of Tokyo, Tokyo, Japan |
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Reperfusion after a transient
ischemia is a frequently encountered clinical condition that often causes
greater tissue damage than persistent ischemia itself. Reperfusion to rabbit
brain, after a transient focal ischemia, induced neutrophil infiltration
and aggregation--neither of which were observed in rabbit brain rendered
ischemic alone for the same time interval--thereby leading to severe brain
edema and infarct. Brain tissue levels of interleukin-8 (IL-8), a potent
neutrophil chemotactic cytokine (chemokine), increased significantly at
6 hours after reperfusion, but without a noticeable elevation of plasma
IL-8 levels. Moreover, we detected IL-8 protein immunohistologically in
the vascular wall and, to a lesser degree, in infiltrated neutrophils, suggesting
a local production of IL-8 in reperfused brain tissues. Furthermore, a neutralizing
anti-IL-8 antibody significantly reduced brain edema and infarct size in
comparison to rabbits receiving a control antibody. These results implicate
locally produced IL-8 as a pivotal mediator of cerebral reperfusion and
suggest that IL-8 is a novel target for the intervention of this injury.
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