Institute for Environmental Medicine, Univ. of Pennsylvania, 3620 Hamilton Walk, 1 John Morgan Bldg., Philadelphia, PA 19104.
Am J Physiol Lung Cell Mol Physiol. 2014 Apr 1;306(7):L635-44. doi: 10.1152/ajplung.00374.2013. Epub 2014 Jan 31.
The phospholipase A2 activity of peroxiredoxin 6 is inhibited by the transition state analog, 1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol (MJ33). This activity is required for the activation of NADPH oxidase, type 2. The present study evaluated the effect of MJ33 on manifestations of acute lung injury. Mice were injected intratracheally (IT) with LPS from Escherichia coli 0111:B4 (LPS, 1 or 5 mg/kg), either concurrently with LPS or 2 h later, and evaluated for lung injury 24 h later. MJ33 inhibited reactive oxygen species (ROS) generation by lungs when measured at 24 h after LPS. LPS at either a low or high dose significantly increased lung infiltration with inflammatory cells, secretion of proinflammatory cytokines (IL-6, TNF-α, and the chemokine macrophage inflammatory protein-2), expression of lung vascular cell adhesion molecule, lung permeability (protein in bronchoalveolar lavage fluid, leakage of FITC-dextran, lung wet-to-dry weight ratio), tissue lipid peroxidation (thiobarbituric acid reactive substances, 8-isoprostanes), tissue protein oxidation (protein carbonyls), and activation of NF-κB. MJ33, given either concurrently or 2 h subsequent to LPS, significantly reduced all of these measured parameters. Previous studies of toxicity showed a high margin of safety for MJ33 in the intact mouse. Thus we have identified MJ33 as a potent, nontoxic, and specific mechanism-based inhibitor of NADPH oxidase type 2-mediated ROS generation that protects mice against lung injury associated with inflammation.
过氧化物酶 6 的磷酸脂酶 A2 活性被过渡态类似物 1-十六烷基-3-(三氟乙基)-sn-甘油-2-磷酸甲醇（MJ33）抑制。这种活性对于 NADPH 氧化酶 2 型的激活是必需的。本研究评估了 MJ33 对急性肺损伤表现的影响。小鼠通过气管内注射大肠杆菌 0111:B4 的脂多糖（LPS，1 或 5mg/kg），与 LPS 同时或 2 小时后注射，并在 24 小时后评估肺损伤。MJ33 抑制了 LPS 24 小时后肺部活性氧（ROS）的生成。低剂量或高剂量 LPS 均显著增加了肺部炎症细胞浸润、促炎细胞因子（IL-6、TNF-α 和趋化因子巨噬细胞炎症蛋白-2）的分泌、肺血管细胞黏附分子的表达、肺通透性（支气管肺泡灌洗液中的蛋白、FITC-右旋糖酐的泄漏、肺湿重/干重比）、组织脂质过氧化（硫代巴比妥酸反应物质、8-异前列腺素）、组织蛋白氧化（蛋白羰基）和 NF-κB 的激活。MJ33 与 LPS 同时或 2 小时后给予，显著降低了所有这些测量参数。先前的毒性研究表明，在完整的小鼠中，MJ33 具有很高的安全性。因此，我们已经确定 MJ33 是一种有效的、非毒性的、特异性的 NADPH 氧化酶 2 型介导的 ROS 生成的机制基础抑制剂，可保护小鼠免受与炎症相关的肺损伤。
