Preexposure to hyperoxia causes increased lung injury and epithelial apoptosis in mice ventilated with high tidal volumes

Patrudu S. Makena, Charlean L. Luellen, Louisa Balazs, Manik C. Ghosh, Kaushik Parthasarathi, Christopher M. Waters, Scott E. Sinclair

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Both high tidal volume mechanical ventilation (HV) and hyperoxia (HO) have been implicated in ventilator-induced lung injury. However, patients with acute lung injury are often exposed to HO before the application of mechanical ventilation. The potential priming of the lungs for subsequent injury by exposure to HO has not been extensively studied. We provide evidence that HO (90%) for 12 h followed by HV (25 μl/g) combined with HO for 2 or 4 h (HO-12hαHVHO-2h or -4h) induced severe lung injury in mice. Analysis of lung homogenates showed that lung injury was associated with cleavage of executioner caspases, caspases-3 and -7, and their downstream substrate poly(ADP-ribose) polymerase-1 (PARP-1). No significant lung injury or caspase cleavage was seen with either HO for 16 h or HV for up to 4 h. Ventilation for 4 h with HO (HVHO) did not cause significant lung injury without preexposure to HO. Twelve-hour HO followed by lower tidal volume (6 μl/g) mechanical ventilation failed to produce significant injury or caspase cleavage. We also evaluated the initiator caspases, caspases-8 and -9, to determine whether the death receptor or mitochondrial-mediated pathways were involved. Caspase-9 cleavage was observed in HO-12h+HVHO-2h and -4h as well as HO for 16 h. Caspase-8 activation was observed only in HO-12h+HVHO-4h, indicating the involvement of both pathways. Immunohistochemistry and in vitro stretch studies showed caspase cleavage in alveolar epithelial cells. In conclusion, preexposure to HO followed by HV produced severe lung injury associated with alveolar epithelial cell apoptosis.

Original languageEnglish
Pages (from-to)L711-L719
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number5
StatePublished - Nov 2010


  • Mechanical ventilation
  • Mouse

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology


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