Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent on oxidant-mediated c-Jun NH 2-terminal kinase activation

Patrudu S. Makena, Vijay K. Gorantla, Manik C. Ghosh, Lavanya Bezawada, Louisa Balazs, Charlean Luellen, Kaushik Parthasarathi, Christopher Waters, Scott Sinclair

Research output: Contribution to journalArticle

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Abstract

Both prolonged exposure to hyperoxia and large tidal volume mechanical ventilation can each independently cause lung injury. However, the combined impact of these insults is poorly understood. We recently reported that preexposure to hyperoxia for 12 h, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone (Makena et al. Am J Physiol Lung Cell Mol Physiol 299: L711-L719, 2010). The upstream mechanisms of this lung injury and apoptosis have not been clearly elucidated. We hypothesized that lung injury in this model was dependent on oxidative signaling via the c-Jun NH 2-terminal kinases (JNK). We, therefore, evaluated lung injury and apoptosis in the presence of N-acetyl-cysteine (NAC) in both mouse and cell culture models, and we provide evidence that NAC significantly inhibited lung injury and apoptosis by reducing the production of ROS, activation of JNK, and apoptosis. To confirm JNK involvement in apoptosis, cells treated with a specific JNK inhibitor, SP600125, and subjected to preexposure to hyperoxia, followed by mechanical stretch, exhibited significantly reduced evidence of apoptosis. In conclusion, lung injury and apoptosis caused by preexposure to hyperoxia, followed by high tidal volume mechanical ventilation, induces ROS-mediated activation of JNK and mitochondrial-mediated apoptosis. NAC protects lung injury and apoptosis by inhibiting ROS-mediated activation of JNK and downstream proapoptotic signaling.

Original languageEnglish (US)
Pages (from-to)1467-1476
Number of pages10
JournalJournal of Applied Physiology
Volume111
Issue number5
DOIs
StatePublished - Nov 1 2011

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Hyperoxia
Tidal Volume
Lung Injury
Artificial Respiration
Oxidants
Phosphotransferases
Apoptosis
Cysteine
MAP Kinase Kinase 4
Ventilation
Cell Culture Techniques
Epithelial Cells
Lung

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

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Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent on oxidant-mediated c-Jun NH 2-terminal kinase activation. / Makena, Patrudu S.; Gorantla, Vijay K.; Ghosh, Manik C.; Bezawada, Lavanya; Balazs, Louisa; Luellen, Charlean; Parthasarathi, Kaushik; Waters, Christopher; Sinclair, Scott.

In: Journal of Applied Physiology, Vol. 111, No. 5, 01.11.2011, p. 1467-1476.

Research output: Contribution to journalArticle

Makena, Patrudu S. ; Gorantla, Vijay K. ; Ghosh, Manik C. ; Bezawada, Lavanya ; Balazs, Louisa ; Luellen, Charlean ; Parthasarathi, Kaushik ; Waters, Christopher ; Sinclair, Scott. / Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent on oxidant-mediated c-Jun NH 2-terminal kinase activation. In: Journal of Applied Physiology. 2011 ; Vol. 111, No. 5. pp. 1467-1476.
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