ENZYCHEM Lifesciences, Seoul, South Korea.
Division of Systems Biology and Bioengineering, Cell Factory Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
Front Immunol. 2019 Sep 18;10:2177. doi: 10.3389/fimmu.2019.02177. eCollection 2019.
Acute lung injury (ALI) is an acute respiratory failure that is associated with excessive neutrophil recruitment and high mortality. To assess the efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a therapeutic agent for ALI, this compound was administered orally to mice challenged with an intranasal dose of lipopolysaccharide (LPS). Using this model, we found that PLAG promotes resolution of ALI through effective control of LPS-induced neutrophil infiltration, endothelial permeability, and inflammatory chemokine production. In addition, the Toll like Receptor 4 (TLR4) endocytosis/exocytosis cycle was significantly accelerated in Raw 264.7 cells co-treated with PLAG/LPS, as compared to cells treated only with LPS. During this cycle, a PLAG-induced exotoxin clearance pathway was observed to occur through the prompt assembly of nicotinamide adenine dinucleotide phosphate (NADPH) units and production of reactive oxygen species (ROS), which ultimately lead to earlier LPS clearance. We further detected reduced expression, as well as faster return to homeostatic levels, of macrophage inflammatory protein (MIP)-2, in PLAG/LPS- vs. LPS-treated cells. MIP-2 is a main inducer of neutrophil migration that is mainly controlled by interferon regulatory factor 3 (IRF3) activation and is involved in the TLR4 endosomal-signaling pathway. PLAG induced TLR4-mediated TRIF-related adaptor molecules/Toll-interleukin receptor (TIR) domain-containing adaptor protein including interferon (IFN)-β/IRF3 endosomal signaling, leading to rapid association of TRAM/TRIF and TLR4 and earlier IRF3 phosphorylation in PLAG/LPS-treated vs. LPS-treated cells. PLAG specificity was further verified with PLAG analogs and metabolites known to control excessive neutrophil infiltration, suggesting that this acetylated diacylglycerol has a unique biological role in neutrophil motility. Thus, our data indicate that PLAG may represent a potential therapeutic agent for resolution of LPS-induced lung inflammation through effective MIP-2 modulation.
急性肺损伤（ALI）是一种与过度中性粒细胞募集和高死亡率相关的急性呼吸衰竭。为了评估 1-棕榈酰基-2-亚油酰基-3-乙酰基-rac-甘油（PLAG）作为 ALI 治疗剂的疗效，将该化合物口服给予接受鼻内脂多糖（LPS）剂量挑战的小鼠。使用该模型，我们发现 PLAG 通过有效控制 LPS 诱导的中性粒细胞浸润、内皮通透性和炎症趋化因子产生，促进 ALI 的解决。此外，与仅用 LPS 处理的细胞相比，PLAG/LPS 共处理的 Raw 264.7 细胞中 Toll 样受体 4（TLR4）内吞/外排循环明显加速。在此循环中，观察到 PLAG 诱导的外毒素清除途径通过烟酰胺腺嘌呤二核苷酸磷酸（NADPH）单元的迅速组装和活性氧（ROS）的产生而发生，这最终导致 LPS 更早清除。我们进一步检测到，与 LPS 处理的细胞相比，PLAG/LPS 处理的细胞中巨噬细胞炎症蛋白（MIP）-2 的表达降低，并且更快地恢复到稳态水平。MIP-2 是中性粒细胞迁移的主要诱导剂，主要受干扰素调节因子 3（IRF3）激活控制，并参与 TLR4 内体信号通路。PLAG 诱导 TLR4 介导的 TRIF 相关衔接分子/Toll-白细胞介素受体（TIR）结构域包含衔接蛋白包括干扰素（IFN）-β/IRF3 内体信号，导致 PLAG/LPS 处理的细胞中 TRAM/TRIF 与 TLR4 的快速关联以及更早的 IRF3 磷酸化。用已知控制过度中性粒细胞浸润的 PLAG 类似物和代谢物进一步验证了 PLAG 的特异性，表明这种乙酰化二酰基甘油在中性粒细胞运动中具有独特的生物学作用。因此，我们的数据表明，PLAG 可能代表一种通过有效调节 MIP-2 来解决 LPS 诱导的肺炎症的潜在治疗剂。
