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-12h+HVHO-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.