Reperfusion injury pathophysiology in sickle transgenic mice

Reperfusion of tissues after interruption of their vascular supply causes f ree-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 generatio n in sickle transgenic mice. Compared with normal mice, sickle mice at ambi ent air had a higher ethane excretion (marker of lipid peroxidation) and gr eater conversion of salicylic acid to 2,3-dihydroxybenzoic acid (marker of hydroxyl radical generation). During hypoxia (11% O-2), only sickle mice co nverted tissue xanthine dehydrogenase to oxidase. Only the sickle mice exhi bited a further increase in ethane excretion during restitution of normal o xygen tension after 2 hours of hypoxia. Only the sickle mice showed abnorma l activation of nuclear factor-kappa B after exposure to hypoxia-reoxygenat ion. Allopurinol, a potential therapeutic agent, decreased ethane excretion in the sickle mice. Thus, sickle transgenic mice exhibit biochemical foot- prints consistent with excessive free-radical generation even at ambient ai r and following a transient induction of enhanced sickling. We suggest that reperfusion injury physiology may contribute to the evolution of the chron ic organ damage characteristic of sickle cell disease. If so, novel therape utic approaches might be of value. (Blood. 2000;96:314-320) (C) 2000 by The American Society of Hematology.