Protection against LPS-induced acute lung injury by a mechanism-based inhibitor of NADPH oxidase (type 2)
Protection against LPS-induced acute lung injury by a mechanism-based inhibitor of NADPH oxidase (type 2)
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DOI：
10.1152/ajplung.00374.2013
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发表时间：
2014-04-01
影响因子：
4.9
通讯作者：
Fisher, Aron B.
中科院分区：
文献类型：
--
作者：
Lee, Intae;Dodia, Chandra;Fisher, Aron B.
过氧化物氧还蛋白6的磷脂酶A（2）活性被过渡态类似物1-十六烷基-3-（三氟乙基）-sn-甘油基-2-磷酸甲醇（MJ 33）抑制。这种活性是激活NADPH氧化酶2型所必需的。本研究评价了MJ 33对急性肺损伤表现的影响。小鼠气管内（IT）注射来自大肠杆菌0111：B4的LPS（LPS，1或5 mg/kg），与LPS同时注射或2 h后注射，24 h后评价肺损伤。当在LPS后24小时测量时，MJ 33抑制肺的活性氧（ROS）产生。低剂量或高剂量LPS均显著增加肺内炎性细胞浸润，促炎细胞因子分泌，（IL-6、TNF-α和趋化因子巨噬细胞炎性蛋白-2）、肺血管细胞粘附分子表达、肺通透性（支气管肺泡灌洗液中的蛋白质、FITC-葡聚糖渗漏、肺湿干重比）、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-κ B活化。MJ 33，同时或2小时后给予LPS，显着降低所有这些测量参数。先前的毒性研究显示，MJ 33在完整小鼠中具有较高的安全范围。因此，我们已经确定MJ 33是一种有效的，无毒的，基于特定机制的NADPH氧化酶2型介导的ROS生成抑制剂，可保护小鼠免受与炎症相关的肺损伤。
The phospholipase A(2) 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-alpha, 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-kappa B. 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.