| Full text | |
| Author(s): |
Almeida, Camila Bononi
[1]
;
Scheiermann, Christoph
[2]
;
Jang, Jung-Eun
[2, 3, 4]
;
Prophete, Colette
[2]
;
Costa, Fernando Ferreira
[1]
;
Conran, Nicola
[1]
;
Frenette, Paul S.
[2, 3, 4]
Total Authors: 7
|
| Affiliation: | [1] Univ Estadual Campinas, INCTS, Hematol & Hemotherapy Ctr, BR-13083970 Campinas, SP - Brazil
[2] Albert Einstein Coll Med, Ruth L & David S Gottesman Inst Stem Cell & Regen, Bronx, NY 10461 - USA
[3] Mt Sinai Sch Med, Dept Med, New York, NY - USA
[4] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY - USA
Total Affiliations: 4
|
| Document type: | Journal article |
| Source: | Blood; v. 120, n. 14, p. 2879-2888, OCT 4 2012. |
| Web of Science Citations: | 38 |
| Abstract | |
Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-alpha-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease. (Blood. 2012; 120(14): 2879-2888) (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 |
| FAPESP's process: | 07/58533-3 - Role of leukocytes in the pathophysiology of sickle cell anemia |
| Grantee: | Camila Bononi de Almeida |
| Support Opportunities: | Scholarships in Brazil - Doctorate |