Department of Medicine, University of Tennessee Health Science Center, Memphis, USA.
Am J Respir Cell Mol Biol. 2012 Apr;46(4):461-9. doi: 10.1165/rcmb.2011-0234OC. Epub 2011 Nov 3.
Both hyperoxia and mechanical ventilation can independently cause lung injury. In combination, these insults produce accelerated and severe lung injury. We recently reported that pre-exposure to hyperoxia for 12 hours, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone. We also reported that such injury and apoptosis are inhibited by antioxidant treatment. In this study, we hypothesized that apoptosis signal-regulating kinase-1 (ASK-1), a redox-sensitive, mitogen-activated protein kinase kinase kinase, plays a role in lung injury and apoptosis in this model. To determine the role of ASK-1 in lung injury, the release of inflammatory mediators and apoptosis, attributable to 12 hours of hyperoxia, were followed by large tidal volume mechanical ventilation with hyperoxia. Wild-type and ASK-1 knockout mice were subjected to hyperoxia (Fi(O(2)) = 0.9) for 12 hours before 4 hours of large tidal mechanical ventilation (tidal volume = 25 μl/g) with hyperoxia, and were compared with nonventilated control mice. Lung injury, apoptosis, and cytokine release were measured. The deletion of ASK-1 significantly inhibited lung injury and apoptosis, but did not affect the release of inflammatory mediators, compared with the wild-type mice. ASK-1 is an important regulator of lung injury and apoptosis in this model. Further study is needed to determine the mechanism of lung injury and apoptosis by ASK-1 and its downstream mediators in the lung.
高氧和机械通气均可独立引起肺损伤。两者联合作用会导致加速和严重的肺损伤。我们最近的研究报道，与单独接受高氧或大潮气量通气相比，预先接受 12 小时高氧暴露，随后进行大潮气量通气，会导致明显的肺损伤和上皮细胞凋亡。我们还报道抗氧化治疗可抑制这种损伤和凋亡。在本研究中，我们假设凋亡信号调节激酶-1（ASK-1）作为一种氧化还原敏感的丝裂原激活蛋白激酶激酶激酶，在该模型的肺损伤和凋亡中发挥作用。为了确定 ASK-1 在肺损伤中的作用，我们对高氧暴露 12 小时后引发的炎症介质释放和细胞凋亡进行了研究，随后进行高氧大潮气量机械通气。野生型和 ASK-1 敲除型小鼠在高氧（Fi(O(2)) = 0.9）中暴露 12 小时后，再进行 4 小时高氧大潮气量机械通气（潮气量=25 μl/g），并与未通气的对照组小鼠进行比较。测量肺损伤、凋亡和细胞因子释放。与野生型小鼠相比，ASK-1 的缺失显著抑制了肺损伤和凋亡，但对炎症介质的释放没有影响。ASK-1 是该模型中肺损伤和凋亡的重要调节因子。需要进一步研究以确定 ASK-1 及其下游介质在肺中的肺损伤和凋亡的机制。
