Synergistic production of lung free radicals by diesel exhaust particles and endotoxin
Synergistic production of lung free radicals by diesel exhaust particles and endotoxin
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DOI：
10.1164/rccm.200402-248oc
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发表时间：
2005-02-15
影响因子：
24.7
通讯作者：
Mason, RP
中科院分区：
文献类型：
--
作者：
Arimoto, T;Kadiiska, MB;Mason, RP
本研究验证了自由基参与柴油机尾气颗粒物（DEP）和细菌脂多糖（LPS）所致肺损伤的发病机制的假说。DEP和LIPS在大鼠肺内共滴入导致肺内自由基产生的协同增强。通过电子自旋共振（ESR）将自由基代谢物表征为脂质衍生物。总蛋白的协同增加和肺支气管肺泡灌洗液（BAL）中中性粒细胞的浸润抑制了自由基的产生。用NADPH还原型（NADPH）氧化酶和iNOS敲除小鼠进行的实验表明，NADPH氧化酶和iNOS对自由基的产生没有贡献。然而，预处理与巨噬细胞毒物GdCl 3，黄嘌呤氧化酶（XO）抑制剂别嘌呤醇，和铁-III螯合剂Desferal导致自由基生成，肺部炎症，肺损伤显着减少。这些作用与抑制肺泡灌洗液中XO活性同时发生，提示激活的巨噬细胞和XO活性参与了DEP和LPS引起的自由基生成。这是第一次证明DEP和LPS协同作用，以增强肺中的自由基产生，通过激活局部XO介导。
The present study tested the hypothesis that free radicals were involved in the pathogenesis of lung injury caused by diesel exhaust particles (DEP) and bacterial lipopolysaccharides (LPS). Intratracheal coinstillation of DEP and LIPS in rat lungs resulted in synergistic enhancement of free radical generation in the lungs. The radical metabolites were characterized as lipid-derived by electron spin resonance (ESR). The free radical generation was paralleled by a synergistic increase in total protein and by infiltration of neutrophils in the bronchoalveolar lavage (BAL) fluid of the lungs. Experiments with NADP-reduced (NADPH) oxidase and iNOS knockout mice showed that NADPH oxidase and iNOS did not contribute to free radical generation. However, pretreatment with the macrophage toxicant GdCl3, the xanthine oxidase (XO) inhibitor allopurinol, and the Fe-III chelator Desferal resulted in a marked decrease in free radical generation, lung inflammation, and lung injury. These effects were concomitant with the inhibition of XO activity in BAL, suggesting that the activated macrophages and the activity of XO contributed to the generation of free radicals caused by DEP and LPS. This is the first demonstration that DEP and LPS work synergistically to enhance free radical generation in lungs, mediated by the activation of local XO.