Lapping-Carr Gabrielle, Khalyfa Abdelnaby, Rangel Stephanie, Darlington Wendy, Beyer Eric C, Peddinti Radhika, Cunningham John M, Gozal David
Sections of Pediatric Hematology-Oncology,, Department of Pediatrics, Comer Children's Hospital, The University of Chicago, Chicago, Illinois.
Department of Pediatrics, Section of Pediatric, Pulmonology and Sleep Medicine, Comer Children's Hospital, The University of Chicago, Chicago, Illinois.
Pediatr Pulmonol. 2017 Nov;52(11):1478-1485. doi: 10.1002/ppul.23698. Epub 2017 May 9.
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.
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.
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.
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.
急性胸综合征（ACS）是镰状细胞病（SCD）患儿的主要死因之一。微血管完整性的破坏是ACS病理生理学的关键，但对其表型变异的影响因素尚不完全清楚。由于循环外泌体与多种疾病的血管功能障碍有关，我们推测外泌体可诱导ACS患者的内皮功能障碍。
横断面队列研究，纳入33例SCD门诊患者（无新的与健康相关的主诉或近期输血史）和一组对照患者。从无血小板血浆中分离外泌体。
ImageStream显示，与对照组相比，SCD患者的外泌体数量大幅增加，但经历过ACS的患者（ACS(+)）和未经历过ACS的患者（ACS(-)）之间外泌体浓度差异不大。将外泌体添加到人微血管内皮细胞中，使用细胞-基质电阻抗传感（ECIS）测定外泌体对单层完整性的影响。未发生ACS的SCD患者的外泌体与对照患者的外泌体差异极小；然而，与ACS(-)相比，ACS(+)患者的外泌体降低了内皮细胞电阻（相对电阻：ACS(+)：0.981±0.055 vs ACS(-)：1.124±0.042；P = 0.006）。用ACS(-)患者的外泌体处理内皮细胞培养物可增加内皮型一氧化氮合酶（eNOS）mRNA表达，而ACS(+)来源的外泌体无法使eNOS表达高于对照组。
这些发现表明，SCD患者循环中的外泌体产生的不同影响可能有助于ACS的病理生理过程，并可能作为与风险相关的生物标志物。
