Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea

Author(s)

Almeida, Camila Bononi ^{[1, 2]} ; Botelho Souza, Lucas Eduardo ^[3] ; Leonardo, Flavia Costa ^[2] ; Maranhao Costa, Fabio Trindade ^[4] ; Werneck, Claudio C. ^[5] ; Covas, Dimas Tadeu ^[3] ; Costa, Fernando Ferreira ^[2] ; Conran, Nicola ^[2]

Affiliation

^[1] Hosp Israelita Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo - Brazil

^[2] Univ Estadual Campinas, UNICAMP, Hematol Ctr, Campinas, SP - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, BR-14049 Ribeirao Preto - Brazil

^[4] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut & Bioagents, Campinas, SP - Brazil

^[5] Univ Estadual Campinas, Inst Biol, Dept Biochem & Tissue Biol, Campinas, SP - Brazil

• Document type: Journal article
• Source: Blood; v. 126, n. 6, p. 711-720, AUG 6 2015.
• Web of Science Citations: 38

Abstract

Hemolysis and consequent release of cell-free hemoglobin (CFHb) impair vascular nitric oxide (NO) bioavailability and cause oxidative and inflammatory processes. Hydroxyurea (HU), a common therapy for sickle cell disease (SCD), induces fetal Hb production and can act as an NO donor. We evaluated the acute inflammatory effects of intravenous water-induced hemolysis in C57BL/6 mice and determined the abilities of an NO donor, diethylamine NONOate (DEANO), and a single dose of HU to modulate this inflammation. Intravenous water induced acute hemolysis in C57BL/6 mice, attaining plasma Hb levels comparable to those observed in chimeric SCD mice. This hemolysis resulted in significant and rapid systemic inflammation and vascular leukocyte recruitment within 15 minutes, accompanied by NO metabolite generation. Administration of another potent NO scavenger (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) to C57BL/6 mice induced similar alterations in leukocyte recruitment, whereas hemin-induced inflammation occurred over a longer timeframe. Importantly, the acute inflammatory effects of water-induced hemolysis were abolished by the simultaneous administration of DEANO or HU, without altering CFHb, in an NO pathway mediated manner. In vitro, HU partially reversed the Hb-mediated induction of endothelial proinflammatory cytokine secretion and adhesion molecule expression. In summary, pathophysiological levels of hemolysis trigger an immediate inflammatory response, possibly mediated by vascular NO consumption. HU presents beneficial anti-inflammatory effects by inhibiting rapid-onset hemolytic inflammation via an NO-dependent mechanism, independently of fetal Hb elevation. Data provide novel insights into mechanisms of hemolytic inflammation and further support perspectives for the use of HU as an acute treatment for SCD and other hemolytic disorders. (AU)

• FAPESP's process: 11/50959-7 - Standardization of transgenic sickle mice bone marrow transplantation, inflammatory induction and assessment of in vivo platelets role in vaso-occlusion
• Grantee: Camila Bononi de Almeida
• Support Opportunities: Scholarships in Brazil - Post-Doctoral