title: The irreversibly sickled cell: a perspective.
abstract: The irreversibly sickled cell (ISC) is poorly deformable, dehydrated, of short life span, correlated to hemolysis, and a contributor to the pathophysiology of vaso-occlusive (VOC) episodes. The altered redox status and increased oxygen radical levels within high density sickle cells leads to oxidative damage and glutathiolation of cysteine residues. The formation of a disulfide bridge between Cys 284 and Cys 373 in ISC beta-actin leads to actin filaments which depolymerize poorly at 37 degrees C. Glutathiolation of cysteines within spectrin results in this key membrane skeletal protein losing it's E2/E3 ubiquitin-ligating/conjugating activity and therefore ability to self ubiquitinate. The resulting loss of ubiquitination in ISC alpha-spectrin repeats 20/21 causes a higher affinity ISC spectrin-4.1-actin ternary complex. Therefore, reversible oxidative damage to beta-actin and loss of ubiquitination of alpha-spectrin leads to an ISC membrane skeleton that disassembles poorly at 37 degrees C. The result is a membrane skeleton which is "locked" because it cannot disassemble or reassemble. N-acetylcysteine (NAC) is an antioxidant which raises intracellular reduced glutathione levels, and blocks the formation of ISCs in vitro. NAC, in a phase II human trial, caused a downward trend in ISCs, significantly decreased dense cells, and substantially decreased the rate of VOC episodes.
authors.affiliation: The Sickle Cell Disease Research Center, The Institute of Biomedical Sciences and Technology, The University of Texas at Dallas, Richardson, Texas 75083, USA. sgoodmn@utdalles.edu
authors.forename: S R
authors.initials: SR
authors.lastname: Goodman
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D003681:Dehydration / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D027981:Symporters / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D000111:Acetylcysteine; D027981:Symporters; D000096922:K Cl- Cotransporters