title: Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice.
abstract: The prevention of organ damage and early death in young adults is a major clinical concern in sickle cell disease (SCD). However, mechanisms that control adult progression of SCD during the transition from adolescence are poorly defined with no cognate prophylaxis. Here, we demonstrate in a longitudinal cohort of homozygous SCD (SS) mice a link between intravascular hemolysis, vascular inflammation, lung injury, and early death. Prophylactic Nrf2 activation in young SS mice stabilized intravascular hemolysis, reversed vascular inflammation, and attenuated lung edema in adulthood. Enhanced Nrf2 activation in endothelial cells in vitro concurred with the dramatic effect on vascular inflammation in the mice. BM chimeric SS mice lacking Nrf2 expression in nonhematopoietic tissues were created to dissect the role of nonerythroid Nrf2 in SCD progression. The SS chimeras developed severe intravascular hemolysis despite having erythroid Nrf2. In addition, they developed premature vascular inflammation and pulmonary edema and died younger than donor littermates with intact nonhematopoietic Nrf2. Our results reveal a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD. Furthermore, we show that prophylactic augmentation of Nrf2-coordinated cytoprotection effectively impedes onset of the severe adult phenotype of SCD in mice.
authors.affiliation: Division of Hematology/Oncology, and.|Center for Translational and International Hematology, Vascular Medicine Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Samit
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Center for Translational and International Hematology, Vascular Medicine Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Chibueze A
authors.initials: CA
authors.lastname: Ihunnah
authors.affiliation: Center for Translational and International Hematology, Vascular Medicine Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Rimi
authors.initials: R
authors.lastname: Hazra
authors.affiliation: Center for Translational and International Hematology, Vascular Medicine Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Aisha L
authors.initials: AL
authors.lastname: Walker
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hansen
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Archer
authors.affiliation: Division of Hematology/Oncology, and.|Center for Translational and International Hematology, Vascular Medicine Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Amma T
authors.initials: AT
authors.lastname: Owusu-Ansah
authors.affiliation: Division of Hematology/Oncology, and.|Center for Translational and International Hematology, Vascular Medicine Institute, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Solomon F
authors.initials: SF
authors.lastname: Ofori-Acquah