Neutrophil extracellular traps (NETs) are beneficial antibacterial defense structures. However, excessive NETs have also been linked to tissue damage and organ dysfunction. LPS and Gram-negative bacteria induce the formation of reactive oxygen species (ROS)-dependent NETs via the JNK pathway. It was found previously that knockdown of nicotinamide phosphoribosyltransferase (NAMPT) upregulates surfactant protein B (SFTPB or SP-B) and attenuates LPS-induced acute lung injury (ALI) via inhibiting JNK activation. This study investigated the effect of FK866, an intracellular NAMPT inhibitor, on the formation of LPS-induced NETs in mouse bronchoalveolar lavage (BAL) neutrophils and in differentiated HL-60 cells. The results show that inhibition of NAMPT by FK866 suppresses NETs formation in BAL neutrophils from the mice exposed to LPS. FK866 also suppresses NETs formation in the differentiated HL-60 cells stimulated with LPS. Additional data indicate that these effects are mediated by suppressing ROS production at least partly via inhibiting JNK activation and depleting NAD(P)H. The utility of inhibition of intracellular NAMPT may be a potential therapy for LPS-induced NETs-related diseases.

中文翻译：

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烟酰胺磷酸核糖转移酶抑制剂是 LPS 诱导的中性粒细胞胞外陷阱的新型治疗候选药物

中性粒细胞胞外陷阱 (NET) 是有益的抗菌防御结构。然而，过量的 NET 也与组织损伤和器官功能障碍有关。LPS 和革兰氏阴性菌通过 JNK 途径诱导活性氧 (ROS) 依赖性 NET 的形成。先前发现，抑制烟酰胺磷酸核糖基转移酶 (NAMPT) 上调表面活性蛋白 B（SFTPB 或 SP-B），并通过抑制 JNK 激活减轻 LPS 诱导的急性肺损伤 (ALI)。本研究调查了 FK866（一种细胞内 NAMPT 抑制剂）对小鼠支气管肺泡灌洗液 (BAL) 中性粒细胞和分化的 HL-60 细胞中 LPS 诱导的 NET 形成的影响。结果表明，FK866 对 NAMPT 的抑制抑制了暴露于 LPS 的小鼠的 BAL 中性粒细胞中的 NET 形成。FK866 还抑制 LPS 刺激的分化 HL-60 细胞中的 NETs 形成。其他数据表明，这些影响是通过抑制 ROS 产生至少部分通过抑制 JNK 激活和消耗 NAD(P)H 来介导的。抑制细胞内 NAMPT 的效用可能是 LPS 诱导的 NETs 相关疾病的潜在疗法。