title: Deletion of apoptosis signal-regulating kinase-1 prevents ventilator-induced lung injury in mice.
abstract: 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.
authors: Department of Medicine, University of Tennessee Health Science Center, Memphis, USA.
authors: Patrudu S
authors: PS
authors: Makena
authors: Vijay K
authors: VK
authors: Gorantla
authors: Manik C
authors: MC
authors: Ghosh
authors: Lavanya
authors: L
authors: Bezawada
authors: Kathirvel
authors: K
authors: Kandasamy
authors: Louisa
authors: L
authors: Balazs
authors: Charlean L
authors: CL
authors: Luellen
authors: Karin E
authors: KE
authors: Thompson
authors: Kaushik
authors: K
authors: Parthasarathi
authors: Hidenori
authors: H
authors: Ichijo
authors: Christopher M
authors: CM
authors: Waters
authors: Scott E
authors: SE
authors: Sinclair
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D018496:Hyperoxia / Q000201:enzymology; D018836:Inflammation Mediators / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000473:pathology; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse