Reperfusion injury pathophysiology in sickle transgenic mice.
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% O(2)), 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-kappaB 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.
Osarogiagbon
U R
UR
Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA.
Choong
S
S
Belcher
J D
JD
Vercellotti
G M
GM
Paller
M S
MS
Hebbel
R P
RP
D000493:Allopurinol / Q000627:therapeutic use; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D015415:Biomarkers; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004980:Ethane / Q000032:analysis; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006801:Humans; D062385:Hydroxybenzoates / Q000032:analysis; D017665:Hydroxyl Radical / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D012016:Reference Values; D015427:Reperfusion Injury / Q000503:physiopathology*; D020156:Salicylic Acid / Q000493:pharmacokinetics; D014968:Xanthine Dehydrogenase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D015415:Biomarkers; D004791:Enzyme Inhibitors; D006451:Hemoglobin, Sickle; D062385:Hydroxybenzoates; D016328:NF-kappa B; D017665:Hydroxyl Radical; D000493:Allopurinol; C009135:2,3-dihydroxybenzoic acid; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase; D004980:Ethane; D020156:Salicylic Acid