1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol（PLAG）通过有效控制中性粒细胞募集迅速解决LPS诱导的急性肺损伤。,Frontiers in Immunology

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1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol（PLAG）通过有效控制中性粒细胞募集迅速解决LPS诱导的急性肺损伤。
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2019-09-18 , DOI: 10.3389/fimmu.2019.02177
Ha-Reum Lee ₁ , Su-Hyun Shin _{2,

3} , Joo Heon Kim ₄ , Ki-Young Sohn ₁ , Sun Young Yoon ₁ , Jae Wha Kim _{2,

3}

Affiliation

急性肺损伤（ALI）是一种急性呼吸衰竭，与过度嗜中性白细胞募集和高死亡率相关。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的治疗剂的功效，将这种化合物口服给予经鼻内剂量脂多糖（LPS）攻击的小鼠。使用此模型，我们发现PLAG可通过有效控制LPS诱导的中性粒细胞浸润，内皮通透性和炎症趋化因子的产生来促进ALI的消退。此外，与仅用LPS处理的细胞相比，在用PLAG / LPS共同处理的Raw 264.7细胞中，Toll样受体4（TLR4）的内吞/胞吐作用周期显着加快。在这个周期中观察到PLAG诱导的外毒素清除途径是通过迅速组装烟酰胺腺嘌呤二核苷酸磷酸（NADPH）单元和产生活性氧（ROS）产生的，最终导致更早的LPS清除。我们进一步检测到在PLAG / LPS-和LPS处理的细胞中巨噬细胞炎性蛋白（MIP）-2的表达降低，并且更快地回到体内稳态水平。MIP-2是嗜中性白细胞迁移的主要诱导剂，主要由干扰素调节因子3（IRF3）激活控制，并参与TLR4内体信号传导途径。PLAG诱导的TLR4介导的TRIF相关衔接子分子/包含Toll-白介素受体（TIR）域的衔接蛋白，包括干扰素（IFN）-β/ IRF3内体信号传导，导致TRAM / TRIF和TLR4快速关联，以及PLAG / LPS处理和LPS处理的细胞中更早的IRF3磷酸化。PLAG的特异性已通过已知可控制过度嗜中性粒细胞浸润的PLAG类似物和代谢物进一步验证，表明这种乙酰化的二酰基甘油在嗜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可能代表通过有效的MIP-2调节解决LPS诱导的肺部炎症的潜在治疗剂。

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1-Palmitoyl-2-Linoleoyl-3-Acetyl-rac-Glycerol (PLAG) Rapidly Resolves LPS-Induced Acute Lung Injury Through the Effective Control of Neutrophil Recruitment.

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.

更新日期：2019-11-01

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