In vivo inosine protects alveolar epithelial type 2 cells against hyperoxia-induced DNA damage through MAP kinase signaling
In vivo inosine protects alveolar epithelial type 2 cells against hyperoxia-induced DNA damage through MAP kinase signaling
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DOI：
10.1152/ajplung.00278.2004
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发表时间：
2005-03-01
影响因子：
4.9
通讯作者：
Warburton, D
中科院分区：
文献类型：
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作者：
Buckley, S;Barsky, L;Warburton, D
肌苷是一种天然存在的具有抗炎特性的嘌呤，被评估为高氧性肺泡上皮损伤的可能调节剂。肌苷200 mg/kg ip，每日两次，暴露于90%氧气中48小时。分离培养肺泡上皮细胞(AEC2)。从肌苷处理的高氧大鼠分离的AEC2与高氧大鼠的AEC2相比，DNA损伤更小，抗氧化状态更强。高氧时肌苷处理还降低了细胞周期中S和G(2)/M期的AEC2比例，增加了DNA修复酶8-氧鸟嘌呤DNA糖基酶的水平。经肌苷处理的高氧大鼠支气管肺泡灌洗液(BAL)中活性转化生长因子-β的含量是单纯高氧BAL的三倍，Smad2在这些动物分离的AEC2中被激活。肌苷作用于新鲜分离的AEC2和培养24小时的AEC2均可激活ERK1/2，而阻断体外MAPK通路可减弱肌苷的保护作用。综上所述，这些数据表明，在高氧暴露期间肌苷治疗导致通过MEK下游通路介导的保护性信号转导。因此，肌苷在减轻高氧对肺泡上皮损伤方面的潜力可能值得进一步评估。
Inosine, a naturally occurring purine with anti-inflammatory properties, was assessed as a possible modulator of hyperoxic damage to the pulmonary alveolar epithelium. Rats were treated with inosine, 200 mg/kg ip, twice daily during 48-h exposure to >90% oxygen. The alveolar epithelial type 2 cells (AEC2) were then isolated and cultured. AEC2 isolated from inosine-treated hyperoxic rats had less DNA damage and had increased antioxidant status compared with AEC2 from hyperoxic rats. Inosine treatment during hyperoxia also reduced the proportion of AEC2 in S and G(2)/M phases of the cell cycle and increased levels of the DNA repair enzyme 8-oxoguanine DNA glycosylase. Bronchoalveolar lavage (BAL) recovered from hyperoxic, inosine-treated rats contained threefold higher levels of active transforming growth factor-beta than BAL from rats exposed to hyperoxia alone, and Smad2 was activated in AEC2 isolated from these animals. ERK1/2 was activated both in freshly isolated and 24-h-cultured AEC2 by in vivo inosine treatment, whereas blockade of the MAPK pathway in vitro reduced the protective effect of in the vivo inosine treatment. Together, the data suggest that inosine treatment during hyperoxic exposure results in protective signaling mediated through pathways downstream of MEK. Thus inosine may deserve further evaluation for its potential to reduce hyperoxic damage to the pulmonary alveolar epithelium.