Neutrophils and neutrophil extracellular traps (NETs) contribute to the vascular complications of multiple diseases, but their role in systemic sclerosis (SSc) is understudied. We sought to test the hypothesis that NETs are implicated in SSc vasculopathy and that treatment with prostacyclin analogs may ameliorate SSc vasculopathy not only through vasodilation but also by inhibiting NET release. Blood from 125 patients with SSc (87 diffuse cutaneous SSc and 38 limited cutaneous SSc) was collected at a single academic medical center. Vascular complications such as digital ulcers, pulmonary artery hypertension, and scleroderma renal crisis were recorded. The association between circulating NETs and vascular complications was determined using in vitro and ex vivo assays. The impact of the synthetic prostacyclin analog epoprostenol on NET release was determined. Neutrophil activation and NET release were elevated in patients with SSc-associated vascular complications compared to matched patients without vascular complications. Neutrophil activation and NETs positively correlated with soluble E-selectin and VCAM-1, circulating markers of vascular injury. Treatment of patients with digital ischemia with a synthetic prostacyclin analog boosted neutrophil cyclic AMP, which was associated with the blunting of NET release and reduced NETs in circulation. Our study demonstrates an association between NETs and vascular complications in SSc. We also identified the potential for an additional therapeutic benefit of synthetic prostacyclin analogs, namely to reduce neutrophil hyperactivity and NET release in SSc patients.

中文翻译：

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系统性硬化症相关血管病中中性粒细胞胞外陷阱升高以及合成前列环素类似物的抑制


中性粒细胞和中性粒细胞胞外陷阱 (NET) 会导致多种疾病的血管并发症，但它们在系统性硬化症 (SSc) 中的作用尚未得到充分研究。我们试图检验以下假设：NET 与 SSc 血管病变有关，并且前列环素类似物治疗不仅可以通过血管舒张，还可以通过抑制 NET 释放来改善 SSc 血管病变。在一个学术医疗中心收集了 125 名 SSc 患者（87 名弥漫性皮肤 SSc 和 38 名局限性皮肤 SSc）的血液。记录血管并发症，如指溃疡、肺动脉高压和硬皮病肾危象。使用体外和离体测定确定循环 NET 与血管并发症之间的关联。确定了合成前列环素类似物依前列醇对 NET 释放的影响。与没有血管并发症的匹配患者相比，患有 SSc 相关血管并发症的患者中性粒细胞活化和 NET 释放升高。中性粒细胞活化和 NET 与可溶性 E-选择素和 VCAM-1（血管损伤的循环标志物）呈正相关。使用合成前列环素类似物治疗手指缺血患者可增强中性粒细胞环 AMP，这与 NET 释放减弱和循环中 NET 减少有关。我们的研究表明 NET 与 SSc 血管并发症之间存在关联。我们还发现了合成前列环素类似物的额外治疗益处的潜力，即减少 SSc 患者中性粒细胞过度活跃和 NET 释放。