Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Basic Science Department, Microbiology Division, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA.
Cell Immunol. 2024 Sep-Oct;403-404:104860. doi: 10.1016/j.cellimm.2024.104860. Epub 2024 Jul 26.
Modulating SYK has been demonstrated to have impacts on pathogenic neutrophil responses in COVID-19. During sepsis, neutrophils are vital in early bacterial clearance but also contribute to the dysregulated immune response and organ injury when hyperactivated. Here, we evaluated the impact of R406, the active metabolite of fostamatinib, on neutrophils stimulated by LPS. We demonstrate that R406 was able to effectively inhibit NETosis, degranulation, ROS generation, neutrophil adhesion, and the formation of CD16 neutrophils that have been linked to detrimental outcomes in severe sepsis. Further, the neutrophils remain metabolically active, capable of releasing cytokines, perform phagocytosis, and migrate in response to IL-8. Taken together, this data provides evidence of the potential efficacy of utilizing fostamatinib in bacterial sepsis.
SYK 的调节已被证明对 COVID-19 中的致病性中性粒细胞反应有影响。在脓毒症中，中性粒细胞在早期清除细菌方面至关重要，但当过度激活时，也会导致免疫反应失调和器官损伤。在这里，我们评估了 fostamatinib 的活性代谢物 R406 对 LPS 刺激的中性粒细胞的影响。我们证明，R406 能够有效地抑制 NETosis、脱颗粒、ROS 生成、中性粒细胞黏附以及与严重脓毒症不良结局相关的 CD16 中性粒细胞的形成。此外，中性粒细胞仍然具有代谢活性，能够释放细胞因子，进行吞噬作用，并对 IL-8 作出迁移反应。总之，这些数据为在细菌脓毒症中使用 fostamatinib 的潜在疗效提供了证据。
