Division of Rheumatology, Department of Internal Medicine, University of Michigan, 1150 W Medical Center Drive, Ann Arbor, MI, 48109, USA.
Arthritis Res Ther. 2024 Jul 25;26(1):139. doi: 10.1186/s13075-024-03379-6.
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.
中性粒细胞和细胞外陷阱（NETs）与多种疾病的血管并发症有关，但它们在系统性硬化症（SSc）中的作用尚未得到充分研究。我们试图验证以下假设，即 NETs 与 SSc 血管病变有关，并且使用前列环素类似物治疗不仅可以通过血管扩张，而且可以通过抑制 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。记录了血管并发症，如手指溃疡、肺动脉高压和硬皮病肾危象。使用体外和离体测定法确定循环 NETs 与血管并发症之间的关联。确定合成前列环素类似物依前列醇对 NET 释放的影响。
与无血管并发症的匹配患者相比，伴有 SSc 相关血管并发症的患者中性粒细胞活化和 NET 释放增加。中性粒细胞活化和 NETs 与可溶性 E-选择素和 VCAM-1 呈正相关，后者是血管损伤的循环标志物。用合成前列环素类似物治疗手指缺血的患者可增加中性粒细胞环磷酸腺苷（cyclic AMP），这与 NET 释放的减弱和循环中 NETs 的减少有关。
我们的研究表明 NETs 与 SSc 中的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另一种潜在治疗益处，即减少 SSc 患者中性粒细胞的过度活跃和 NET 释放。
