Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 46, Issue 4, Pages 461-469Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2011-0234OC
Keywords
ventilator-induced lung injury; acute lung injury; hyperoxia; apoptosis; apoptosis signal-regulating kinase-1
Funding
- National Heart, Lung, and Blood Institute from the National Institutes of Health [HL-081297, HL-094366]
- Grants-in-Aid for Scientific Research [23659033, 20229004] Funding Source: KAKEN
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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 (FIO2 = 0.9) for 12 hours before 4 hours of large tidal mechanical ventilation (tidal volume = 25 mu l/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.
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