Neutrophil extracellular trap regulators in sickle cell disease: Modulation of gene expression of PADI4, neutrophil elastase, and myeloperoxidase during vaso-occlusive crisis.

Autor: Hounkpe BW; School of Medical Sciences University of Campinas Campinas Brazil., Chenou F; School of Medical Sciences University of Campinas Campinas Brazil., Domingos IF; Federal University of Rio Grande do Norte (UFRN) Recife Brazil., Cardoso EC; Hematology and Hemotherapy Foundation from Amazonas State (HEMOAM) Manaus Brazil., Costa Sobreira MJV; Federal University of Pernambuco (UFPE) Recife Brazil., Araujo AS; Hematology and Hemotherapy Foundation of Pernambuco - HEMOPE Recife Brazil., Lucena-Araújo AR; Federal University of Pernambuco (UFPE) Recife Brazil., da Silva Neto PV; Hematology and Hemotherapy Foundation from Amazonas State (HEMOAM) Manaus Brazil., Malheiro A; Hematology and Hemotherapy Foundation from Amazonas State (HEMOAM) Manaus Brazil., Fraiji NA; Hematology and Hemotherapy Foundation from Amazonas State (HEMOAM) Manaus Brazil., Costa FF; School of Medical Sciences University of Campinas Campinas Brazil.; Hematology and Hemotherapy Center University of Campinas Campinas Brazil., Bezerra MAC; Federal University of Pernambuco (UFPE) Recife Brazil., Santos MNN; School of Medical Sciences University of Campinas Campinas Brazil., De Paula EV; School of Medical Sciences University of Campinas Campinas Brazil.; Hematology and Hemotherapy Center University of Campinas Campinas Brazil.
Jazyk: angličtina
Zdroj: Research and practice in thrombosis and haemostasis [Res Pract Thromb Haemost] 2020 Dec 16; Vol. 5 (1), pp. 204-210. Date of Electronic Publication: 2020 Dec 16 (Print Publication: 2021).
DOI: 10.1002/rth2.12463
Abstrakt: Background: Recent evidence suggests that generation of neutrophil extracellular traps (NETosis), one of the components of immunothrombosis, is associated with the pathogenesis of both venous thromboembolism and sickle cell disease (SCD). NETosis is a complex process regulated by several proteins such as peptidyl arginine deaminase 4 (PADI4), neutrophil elastase (ELANE), and myeloperoxidase (MPO). Among these regulators, PADI4 is responsible of histone citrullination, an essential step for NETosis. Accordingly, its inhibition has been recently cited as a promising therapeutic strategy for diseases such as SCD. Although attractive, this strategy requires supportive evidence of its role in the pathogenesis of SCD.
Patients and Methods: Patients from two independent cohorts were enrolled in this study. Samples were obtained at steady state (53 patients) or during acute episodes of vaso-occlusive crisis (VOC; 28 patients) in patients from cohort 1. mRNA was extracted from granulocytes to analyze PADI4 ,  ELANE , and  MPO  expression by qPCR. Furthermore, plasma activity of PADI4 was assessed from an independent cohort in 15 patients, within 24 hours from admission for VOC. Race-matched healthy individuals from the same geographic regions were used as controls for each cohort.
Results and Conclusions: Higher levels of gene expression of  PADI4 and  ELANE  were observed during VOC. Furthermore, plasma activity of PADI4 was higher in acute VOC when compared to healthy individuals. These results demonstrate that NETosis regulators are modulated during acute VOC, and pave the way for studies of PADI4  inhibition as a therapeutic strategy for acute VOC in SCD.
(© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)
Databáze: MEDLINE
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