Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Am J Physiol Lung Cell Mol Physiol. 2010 Nov;299(5):L711-9. doi: 10.1152/ajplung.00072.2010. Epub 2010 Sep 10.
Both high tidal volume mechanical ventilation (HV) and hyperoxia (HO) have been implicated in ventilator-induced lung injury. However, patients with acute lung injury are often exposed to HO before the application of mechanical ventilation. The potential priming of the lungs for subsequent injury by exposure to HO has not been extensively studied. We provide evidence that HO (90%) for 12 h followed by HV (25 μl/g) combined with HO for 2 or 4 h (HO-12h+HVHO-2h or -4h) induced severe lung injury in mice. Analysis of lung homogenates showed that lung injury was associated with cleavage of executioner caspases, caspases-3 and -7, and their downstream substrate poly(ADP-ribose) polymerase-1 (PARP-1). No significant lung injury or caspase cleavage was seen with either HO for 16 h or HV for up to 4 h. Ventilation for 4 h with HO (HVHO) did not cause significant lung injury without preexposure to HO. Twelve-hour HO followed by lower tidal volume (6 μl/g) mechanical ventilation failed to produce significant injury or caspase cleavage. We also evaluated the initiator caspases, caspases-8 and -9, to determine whether the death receptor or mitochondrial-mediated pathways were involved. Caspase-9 cleavage was observed in HO-12h+HVHO-2h and -4h as well as HO for 16 h. Caspase-8 activation was observed only in HO-12h+HVHO-4h, indicating the involvement of both pathways. Immunohistochemistry and in vitro stretch studies showed caspase cleavage in alveolar epithelial cells. In conclusion, preexposure to HO followed by HV produced severe lung injury associated with alveolar epithelial cell apoptosis.
高容量机械通气（HV）和高氧（HO）均与呼吸机相关性肺损伤有关。然而，急性肺损伤患者在接受机械通气前通常会暴露于高氧中。HO 暴露对随后损伤的潜在“预激”作用尚未得到广泛研究。我们提供的证据表明，12 小时 HO（90%）暴露后紧接着 2 或 4 小时 HV（25 μl/g）联合 HO（HO-12h+HVHO-2h 或 -4h）可诱导小鼠严重的肺损伤。对肺匀浆的分析表明，肺损伤与执行器半胱天冬酶、半胱天冬酶-3 和 -7 及其下游底物多聚（ADP-核糖）聚合酶-1（PARP-1）的裂解有关。16 小时 HO 或长达 4 小时 HV 暴露均未引起明显的肺损伤或半胱天冬酶裂解。在没有预先 HO 暴露的情况下，HO 通气 4 小时也不会引起明显的肺损伤。随后的 6 μl/g 低潮气量机械通气 12 小时未能导致明显的损伤或半胱天冬酶裂解。我们还评估了起始半胱天冬酶、半胱天冬酶-8 和 -9，以确定是否涉及死亡受体或线粒体介导的途径。HO-12h+HVHO-2h 和 -4h 以及 16 小时 HO 均可观察到半胱天冬酶-9 的裂解。仅在 HO-12h+HVHO-4h 中观察到半胱天冬酶-8 的激活，表明两种途径均参与其中。免疫组化和体外拉伸研究显示肺泡上皮细胞中的半胱天冬酶裂解。总之，HO 暴露后继之以 HV 会导致严重的肺损伤，与肺泡上皮细胞凋亡有关。
