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.