Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université Catholique de Louvain (UCLouvain), Brussels, Belgium.
FASEB J. 2019 Jun;33(6):7635-7646. doi: 10.1096/fj.201802259R. Epub 2019 Mar 21.
Lung inflammation plays a crucial role in the pathogenesis of many respiratory diseases that are in need of new therapeutic strategies. Previously, we showed that inhibition of α/β-hydrolase domain 6 (ABHD6) decreased macrophage activation and exerted anti-inflammatory effects. Therefore, we thought to assess the effects of ABHD6 inhibition in a mouse model of acute lung injury (ALI) induced by intratracheal administration of lipopolysaccharides. ABHD6 inhibition with -methyl--{[3-(4-pyridinyl)phenyl]methyl}-carbamic acid 4'-(aminocarbonyl)(1,1'-biphenyl)-4-yl ester (WWL70) decreases most of the hallmarks of ALI, including neutrophil infiltration, cytokine secretion, and protein extravasation. mRNA expression of proinflammatory markers in the cells recovered in the bronchoalveolar lavage was also decreased. Interestingly, ABHD6 inhibition was more efficient than monoacylglycerol lipase inhibition by 4-nitrophenyl-4-[dibenzo(d)(14)dioxol-5-yl(hydroxy)methyl]piperidine-1-carboxylate. We also studied ABHD6 inhibition on primary alveolar macrophages and neutrophils to explore their potential implication in the effects of ABHD6 inhibition . Moreover, we quantified by high-performance liquid chromatography-mass spectrometry the levels of reported substrates of ABHD6 [, 2-arachidonoylglycerol (2-AG) and lysophospholipids]. The potential implication of these lipid mediators in the effects of WWL70 was further investigated on primary alveolar macrophages. Taken together, these data support ABHD6 inhibition as an interesting anti-inflammatory strategy in acute lung inflammation and assess the possible contribution of 2-AG and lysophospholipids in the observed effects.-Bottemanne, P., Paquot, A., Ameraoui, H., Alhouayek, M., Muccioli, G. G. The α/β-hydrolase domain 6 inhibitor WWL70 decreases endotoxin-induced lung inflammation in mice, potential contribution of 2-arachidonoylglycerol, and lysoglycerophospholipids.
肺炎症在许多需要新治疗策略的呼吸道疾病的发病机制中起着关键作用。以前，我们发现抑制 α/β-水解酶结构域 6（ABHD6）可减少巨噬细胞活化并发挥抗炎作用。因此，我们认为评估 ABHD6 抑制在脂多糖气管内给药诱导的急性肺损伤（ALI）小鼠模型中的作用。用 -甲基--{[3-(4-吡啶基)苯基]甲基}-氨基甲酸 4'-(氨基羰基)(1,1'-联苯)-4-基酯（WWL70）抑制 ABHD6 可降低 ALI 的大部分特征，包括中性粒细胞浸润、细胞因子分泌和蛋白外渗。支气管肺泡灌洗液中回收细胞的促炎标志物的 mRNA 表达也降低。有趣的是，ABHD6 抑制比单酰基甘油脂肪酶抑制更有效 4-硝基苯基-4-[二苯并（d）（14）二恶烷-5-基（羟基）甲基]哌啶-1-羧酸盐。我们还研究了 ABHD6 抑制对原代肺泡巨噬细胞和中性粒细胞的作用，以探讨其在 ABHD6 抑制作用中的潜在意义。此外，我们通过高效液相色谱-质谱法定量了报道的 ABHD6 底物的水平[、2-花生四烯酸甘油（2-AG）和溶血磷脂]。进一步在原代肺泡巨噬细胞上研究了这些脂质介质在 WWL70 作用中的潜在意义。总之，这些数据支持 ABHD6 抑制作为急性肺炎症的一种有前途的抗炎策略，并评估了 2-AG 和溶血磷脂在观察到的作用中的可能贡献。-Bottemanne，P.，Paquot，A.，Ameraoui，H.，Alhouayek，M.，Muccioli，G. G. α/β-水解酶结构域 6 抑制剂 WWL70 可降低小鼠内毒素诱导的肺炎症，2-花生四烯酸甘油和溶血甘油磷脂的潜在贡献。
