Reperfusion injury pathophysiology in sickle transgenic mice

Abstract

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–κB 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.

Hydroxyurea (hydroxycarbamide) genotoxicity in pediatric patients with sickle cell disease

“…Hypoxia, in sickle transgenic mice, has been shown to convert tissue xanthine dehydrogenase to oxidase, generating ROS. 23 Similar events could be expected in humans.…”

Mouse models for studying pain in sickle disease: effects of strain, age, and acuteness

“…This was repeated after 24 h, followed by pain measures after 1-2 h, 18 h and 7 d of reoxygenation (HR2). Hypoxia induces an approximate 10-fold increase in sickle RBC in sickle mice but not in normal mice (Osarogiagbon et al, 2000).…”

Lack of Duffy antigen expression is associated with organ damage in patients with sickle cell disease

“…Although the cause of such phenotypic variability is unknown, we now recognize that SCD represents a chronic inflammatory state, [1][2][3] in which inflammation, white blood cell (WBC) adhesion to vascular endothelium, and subsequent endothelial injury, due in part to repeated ischemia-reperfusion injury, contribute to disease pathogenesis. [4][5][6][7] SCD patients have elevated WBC counts, 8 abnormal red blood cell (RBC) adhesion, 5,9 and activation of coagulation pathways. 10 Recent studies have begun to implicate genetic polymorphisms as possible predictors of SCD complications.…”