Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice

• Type of Material: Article
• Authors: Samit Ghosh, University of Pittsburgh; Chibueze Ihunnah, University of Pittsburgh; Rimi Hazra, University of Pittsburgh; Aisha L. Walker, University of Pittsburgh; Jason Hansen, Emory University; David Archer, Emory University; Amma T. Owusu-Ansah, University of Pittsburgh; Solomon F. Ofori-Acquah, University of Pittsburgh
• Language: English
• Date: 2016-04-07
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2016, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.81090
• Title of Journal or Parent Work: JCI Insight
• Volume: 1
• Issue: 4
• Grant/Funding Information: This study was conducted with research funding from the National Heart, Lung and Blood Institute (NHLBI) (Award Number: R01 HL106192 and U01 HL117721).
• Keywords: NUCLEAR EXPORT; Research & Experimental Medicine; DISEASE; Life Sciences & Biomedicine; PULMONARY-HYPERTENSION; Medicine, Research & Experimental; MORTALITY; RISK-FACTORS; CARE; CHILDREN; Science & Technology; HEME OXYGENASE-1; GENE-EXPRESSION; ACUTE CHEST SYNDROME
• Research Categories: Health Sciences, Medicine and Surgery

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.