Deletion of apoptosis signal-regulating kinase-1 prevents ventilator-induced lung injury in mice

Patrudu S. Makena, Vijay K. Gorantla, Manik C. Ghosh, Lavanya Bezawada, Kathirvel Kandasamy, Louisa Balazs, Charlean L. Luellen, Karin E. Thompson, Kaushik Parthasarathi, Hidenori Ichijo, Christopher Waters, Scott Sinclair

Research output: Contribution to journalArticle

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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 O2 = 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.

Original languageEnglish (US)
Pages (from-to)461-469
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume46
Issue number4
DOIs
StatePublished - Apr 1 2012

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MAP Kinase Kinase Kinase 5
Ventilator-Induced Lung Injury
Lung Injury
Hyperoxia
Apoptosis
Tidal Volume
Artificial Respiration
MAP Kinase Kinase Kinases
Ventilation
Knockout Mice
Oxidation-Reduction
Antioxidants
Cytokines
Epithelial Cells

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Deletion of apoptosis signal-regulating kinase-1 prevents ventilator-induced lung injury in mice. / Makena, Patrudu S.; Gorantla, Vijay K.; Ghosh, Manik C.; Bezawada, Lavanya; Kandasamy, Kathirvel; Balazs, Louisa; Luellen, Charlean L.; Thompson, Karin E.; Parthasarathi, Kaushik; Ichijo, Hidenori; Waters, Christopher; Sinclair, Scott.

In: American journal of respiratory cell and molecular biology, Vol. 46, No. 4, 01.04.2012, p. 461-469.

Research output: Contribution to journalArticle

Makena, Patrudu S. ; Gorantla, Vijay K. ; Ghosh, Manik C. ; Bezawada, Lavanya ; Kandasamy, Kathirvel ; Balazs, Louisa ; Luellen, Charlean L. ; Thompson, Karin E. ; Parthasarathi, Kaushik ; Ichijo, Hidenori ; Waters, Christopher ; Sinclair, Scott. / Deletion of apoptosis signal-regulating kinase-1 prevents ventilator-induced lung injury in mice. In: American journal of respiratory cell and molecular biology. 2012 ; Vol. 46, No. 4. pp. 461-469.
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