Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy.
Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Firenze, Firenze, Italy.
Front Immunol. 2019 Dec 13;10:2877. doi: 10.3389/fimmu.2019.02877. eCollection 2019.
Behçet's syndrome (BS) is a systemic vasculitis considered as the prototype of a systemic inflammation-induced thrombotic condition whose pathogenesis cannot be explained just by coagulation abnormalities. Circulating hematopoietic progenitor cells (CPC), a population of rare, pre-differentiated adult stem cells originating in the bone marrow and capable of both self-renewal and multi-lineage differentiation, are mobilized in response to vascular injury and play a key role in tissue repair. In cardiovascular and thrombotic diseases, low circulating CPC number and reduced CPC function have been observed. Oxidative stress may be one of the relevant culprits that account for the dysfunctional and numerically reduced CPC in these conditions. However, the detailed mechanisms underlying CPC number reduction are unknown. On this background, the present study was designed to evaluate for the first time the possible relationship between CPC dysfunction and oxidative stress in BS patients. In BS patients, we found signs of plasma oxidative stress and significantly lower CD34+/CD45 and CD34+/CD45/CD133+ CPC levels. Importantly, in all the considered CPC subsets, significantly higher ROS levels with respect to controls were observed. Higher levels of caspase-3 activity in all the considered CPC population and a strong reduction in GSH content in CPC subpopulation from BS patients with respect to controls were also observed. Interestingly, in BS patients, ROS significantly correlated with CPC number and CPC caspase-3 activity and CPC GSH content significantly correlated with CPC number, in all CPC subsets. Collectively, these data demonstrate for the first time that CPC from BS patients show signs of oxidative stress and apoptosis and that a reduced CPC number is present in BS patients with respect to controls. Interestingly, we observed an inverse correlation between circulating CPC number and CPC ROS production, suggesting a possible toxic ROS effect on CPC in BS patients. The significant correlations between ROS production/GSH content and caspase-3 activity point out that oxidative stress can represent a determinant in the onset of apoptosis in CPC. These data support the hypothesis that oxidative-stress-mediated CPC dysfunctioning may counteract their vascular repair actions, thereby contributing to the pathogenesis and the progression of vascular disease in BS.
白塞病（BS）是一种系统性血管炎，被认为是一种全身性炎症引起的血栓形成疾病的原型，其发病机制不能仅用凝血异常来解释。循环造血祖细胞（CPC）是一种罕见的、未分化的成体干细胞，起源于骨髓，具有自我更新和多谱系分化的能力，在血管损伤时被动员，并在组织修复中发挥关键作用。在心血管和血栓形成疾病中，观察到循环 CPC 数量减少和 CPC 功能降低。氧化应激可能是导致这些情况下 CPC 功能障碍和数量减少的相关罪魁祸首之一。然而，CPC 数量减少的详细机制尚不清楚。在此背景下，本研究旨在首次评估 BS 患者中 CPC 功能障碍与氧化应激之间的可能关系。在 BS 患者中，我们发现了血浆氧化应激的迹象，并且 CD34+/CD45 和 CD34+/CD45/CD133+CPC 水平明显降低。重要的是，与对照组相比，在所有考虑的 CPC 亚群中，观察到 ROS 水平显著升高。在所有考虑的 CPC 群体中，caspase-3 活性水平较高，以及从 BS 患者的 CPC 亚群中观察到 GSH 含量与对照组相比强烈降低。有趣的是，在 BS 患者中，ROS 与 CPC 数量和 CPC caspase-3 活性显著相关，并且在所有 CPC 亚群中，CPC GSH 含量与 CPC 数量显著相关。总的来说，这些数据首次证明，来自 BS 患者的 CPC 显示出氧化应激和细胞凋亡的迹象，并且与对照组相比，BS 患者的 CPC 数量减少。有趣的是，我们观察到循环 CPC 数量与 CPC ROS 产生之间存在负相关，这表明在 BS 患者中，ROS 可能对 CPC 产生毒性作用。ROS 产生/GSH 含量与 caspase-3 活性之间的显著相关性表明，氧化应激可能是 CPC 细胞凋亡的决定因素。这些数据支持这样一种假设，即氧化应激介导的 CPC 功能障碍可能会抵消其血管修复作用，从而导致 BS 中血管疾病的发病机制和进展。
