Recchia Luciani Giulia, Visigalli Rossana, Dall'Asta Valeria, Rotoli Bianca Maria, Barilli Amelia
Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy.
Int J Mol Sci. 2025 Jun 19;26(12):5916. doi: 10.3390/ijms26125916.
Multiple lines of evidence suggest that endothelial dysfunction is a key player in the pathogenesis of COVID-19, with cytokine storm as one of the main primary causes. Among the mechanisms underlying endothelial damage, clinical findings identify alterations in arginine metabolism, as patients with severe COVID-19 exhibit lower levels of nitric oxide synthase (eNOS) and upregulated arginase. In this study, we investigated, in human endothelial cells (HUVECs), the effect of conditioned medium from macrophages activated with SARS-CoV-2 Spike protein (CM_S1) on arginine metabolism. The results indicate that CM_S1 causes a marked decrease in eNOS and an increase in arginase, along with a greater intracellular arginine content and the induction of the CAT2 transporter. These effects are ascribable to the inflammatory mediators released by macrophages in CM_S1, mainly TNFα and IL-1β. Since infliximab, an antibody targeting TNFα, and baricitinib, an inhibitor of the JAK/STAT pathway, correct the observed imbalance between eNOS and arginase, our findings suggest the potential efficacy of a combined therapy to counteract endothelial dysfunction in COVID-19.
多条证据表明，内皮功能障碍是新冠病毒疾病（COVID-19）发病机制中的关键因素，细胞因子风暴是主要的原发性病因之一。在导致内皮损伤的机制中，临床研究发现精氨酸代谢发生改变，因为重症COVID-19患者的一氧化氮合酶（eNOS）水平较低且精氨酸酶上调。在本研究中，我们在人内皮细胞（HUVECs）中研究了用SARS-CoV-2刺突蛋白激活的巨噬细胞条件培养基（CM_S1）对精氨酸代谢的影响。结果表明，CM_S1导致eNOS显著降低、精氨酸酶增加，同时细胞内精氨酸含量更高且诱导了CAT2转运蛋白。这些效应归因于CM_S1中巨噬细胞释放的炎症介质，主要是TNFα和IL-1β。由于靶向TNFα的抗体英夫利昔单抗和JAK/STAT途径抑制剂巴瑞替尼纠正了观察到的eNOS和精氨酸酶之间的失衡，我们的研究结果表明联合治疗在对抗COVID-19内皮功能障碍方面具有潜在疗效。
