Patients with acute respiratory distress syndrome require mechanical ventilation and supplemental oxygen, but animal models demonstrate that the combination of these two factors can contribute to lung injury. We previously showed that pre-exposure of mice to hyperoxia before mechanical ventilation exacerbated ventilator-induced lung injury (VILI), and that deletion of apoptosis signal-regulating kinase-1 (ASK1) ameliorated this effect. We hypothesize that ASK1 promotes VILI through activation of apoptotic pathways and inhibition of cell survival pathways. Using mice pre-treated with hyperoxia (95% oxygen for 12 hr) and then ventilated with an injurious tidal volume (25 ml/kg for 4 hr), we found an increase in apoptotic cells that was reduced in ASK1-/- mice and in wild type mice treated with a p38 inhibitor (SB202190). P38, a downstream effector of ASK1, was activated in untreated wild type mice, but was not activated in ASK1-/- mice. Survivin, a member of the inhibitors of apoptosis protein family, was up-regulated in ASK1-/-, but not wild type mice, in response to hyperoxia and VILI. These data suggest that injury caused by the combined effects of hyperoxia and mechanical ventilation are in part mediated by ASK1, which promotes p38-mediated apoptosis and inhibits survival pathways.
Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB075
Poster Communications: Hyperoxia promotes ventilator-induced lung injury through apoptosis signal-regulating kinase-1 (ASK1)
C. Waters1,2, P. Makena2, S. Sinclair2, C. Luellen1, B. Teng1, C. Immanuel3, J. Kennedy1
1. Physiology, University of Tennessee, Memphis, Tennessee, United States. 2. Medicine, University of Tennessee, Memphis, Tennessee, United States. 3. Pediatrics, University of Tennessee, Memphis, Tennessee, United States.
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