Gabrielle Lapping-Carr1, Abdelnaby Khalyfa2, Stephanie Rangel3, Wendy Darlington1, Eric C Beyer1, Radhika Peddinti1, John M Cunningham1, David Gozal2. 1. Sections of Pediatric Hematology-Oncology,, Department of Pediatrics, Comer Children's Hospital, The University of Chicago, Chicago, Illinois. 2. Department of Pediatrics, Section of Pediatric, Pulmonology and Sleep Medicine, Comer Children's Hospital, The University of Chicago, Chicago, Illinois. 3. Department of Dermatology, Northwestern University, Chicago, Illinois.
Abstract
BACKGROUND: Acute Chest Syndrome (ACS) is one of the leading causes of death among children with Sickle Cell Disease (SCD). Disruption of microvascular integrity is critical to the pathophysiology of ACS, but the factors governing its phenotypic variability are incompletely understood. Because circulating exosomes have been implicated in vascular dysfunction in various diseases, we hypothesized that exosomes induce endothelial dysfunction in patients who experience ACS. PROCEDURE: Cross-sectional cohort study including 33 outpatients with SCD (without new health-related complaints or recent transfusions) and a cohort of control patients. Exosomes were isolated from platelet-free plasma. RESULTS: ImageStream showed that exosome counts were greatly increased in patients with SCD compared with controls, but there were few differences in the concentrations of exosomes between patients who had experienced ACS (ACS(+)) and those who had not (ACS(-)). Exosomes were added to human microvascular endothelial cells, and the exosomal effects on monolayer integrity was determined using Electric Cell-substrate Impedance Sensing (ECIS). Exosomes from SCD patients without ACS differed minimally from control patients; however, exosomes from ACS(+) decreased endothelial cell resistance compared to ACS(-), (Relative resistance: ACS(+): 0.981 ± 0.055 vs ACS(-): 1.124 ± 0.042; P = 0.006). Treatment of endothelial cultures with exosomes from ACS(-) patients increased endothelial Nitric Oxide Synthase (eNOS) mRNA expression, while ACS(+)-derived exosomes were not able to increase eNOS expression above that of controls. CONCLUSIONS: These findings demonstrate that patients with SCD have circulating exosomes that produce differential effects that may contribute to the pathophysiology of ACS and may serve as risk-related biomarkers.
BACKGROUND: Acute Chest Syndrome (ACS) is one of the leading causes of death among children with Sickle Cell Disease (SCD). Disruption of microvascular integrity is critical to the pathophysiology of ACS, but the factors governing its phenotypic variability are incompletely understood. Because circulating exosomes have been implicated in vascular dysfunction in various diseases, we hypothesized that exosomes induce endothelial dysfunction in patients who experience ACS. PROCEDURE: Cross-sectional cohort study including 33 outpatients with SCD (without new health-related complaints or recent transfusions) and a cohort of control patients. Exosomes were isolated from platelet-free plasma. RESULTS: ImageStream showed that exosome counts were greatly increased in patients with SCD compared with controls, but there were few differences in the concentrations of exosomes between patients who had experienced ACS (ACS(+)) and those who had not (ACS(-)). Exosomes were added to human microvascular endothelial cells, and the exosomal effects on monolayer integrity was determined using Electric Cell-substrate Impedance Sensing (ECIS). Exosomes from SCDpatients without ACS differed minimally from control patients; however, exosomes from ACS(+) decreased endothelial cell resistance compared to ACS(-), (Relative resistance: ACS(+): 0.981 ± 0.055 vs ACS(-): 1.124 ± 0.042; P = 0.006). Treatment of endothelial cultures with exosomes from ACS(-)patients increased endothelial Nitric Oxide Synthase (eNOS) mRNA expression, while ACS(+)-derived exosomes were not able to increase eNOS expression above that of controls. CONCLUSIONS: These findings demonstrate that patients with SCD have circulating exosomes that produce differential effects that may contribute to the pathophysiology of ACS and may serve as risk-related biomarkers.
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