PDF(Pubmed)
Abstract：
Clarkson disease, or monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.
摘要：
克拉克森病（单克隆丙种球蛋白病相关特发性系统性毛细血管渗漏综合征，ISCLS)是一种罕见的，复发-缓解性疾病的特征是液体和蛋白质突然外渗到外周组织，进而导致低血压性休克,严重的血液浓缩,和低蛋白血症.ISCLS中的特定渗漏因子和途径未知，对急性耀斑没有有效的治疗方法.在这里，我们描述了ISCLS中的自主血管内皮缺陷，该缺陷在培养物中的患者来源的内皮细胞（ECs）和疾病小鼠模型中进行了概括。ISCLS衍生的ECs对渗透性诱导因子如VEGF和组胺在功能上反应过度，部分原因是内皮型一氧化氮合酶（eNOS）活性增加。通过施用N(γ)-硝基-L-精氨酸甲酯(L-NAME)阻断eNOS改善由组胺或VEGF攻击诱导的ISCLS的SJL/J小鼠模型中的血管渗漏。eNOS的错误定位和蛋白磷酸酶2A（PP2A）表达的减少可能有助于ISCLS衍生的ECs中eNOS的过度激活。我们的发现为ISCLS中的微血管屏障功能障碍提供了机械见解，并强调了潜在的治疗方法。
