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Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 314-320
Reperfusion injury pathophysiology in sickle
transgenic mice
U. Raymond Osarogiagbon,
Stephana Choong,
John D. Belcher,
Gregory M. Vercellotti,
Mark S. Paller, and
Robert P. Hebbel
From the Department of Medicine, University of Minnesota Medical
School, Minneapolis, MN.
Reperfusion of tissues after interruption of their vascular supply
causes free-radical generation that leads to tissue damage, a scenario
referred to as "reperfusion injury." Because sickle disease
involves repeated transient ischemic episodes, we sought evidence for
excessive free-radical generation in sickle transgenic mice. Compared
with normal mice, sickle mice at ambient air had a higher ethane
excretion (marker of lipid peroxidation) and greater conversion of
salicylic acid to 2,3-dihydroxybenzoic acid (marker of hydroxyl radical
generation). During hypoxia (11% O2), only sickle mice
converted tissue xanthine dehydrogenase to oxidase. Only the sickle
mice exhibited a further increase in ethane excretion during
restitution of normal oxygen tension after 2 hours of hypoxia. Only the
sickle mice showed abnormal activation of nuclear factor- B after
exposure to hypoxia-reoxygenation. Allopurinol, a potential therapeutic
agent, decreased ethane excretion in the sickle mice. Thus, sickle
transgenic mice exhibit biochemical footprints consistent with
excessive free-radical generation even at ambient air and following a
transient induction of enhanced sickling. We suggest that reperfusion
injury physiology may contribute to the evolution of the chronic organ
damage characteristic of sickle cell disease. If so, novel therapeutic
approaches might be of value.
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