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J Appl Physiol (July 31, 2008). doi:10.1152/japplphysiol.90689.2008
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Submitted on May 27, 2008
Revised on July 8, 2008
Accepted on July 29, 2008

Alveolar Cell Apoptosis is Dependent on p38-MAPK-Mediated Activation of Xanthine Oxidoreductase in Ventilator-Induced Lung Injury

Anne Le1, Rachel Damico2, Mahendra Damarla2, Adel Boueiz2, Hyun Hae Pae2, Jarrett Skirball2, Emile Hasan2, Xinqi Peng2, Alan Chesley2, Michael T Crow3, Sekhar P Reddy4, Rubin M. Tuder2, and Paul M Hassoun2*

1 Johns Hopkins Medical Institution
2 Johns Hopkins University School of Medicine
3 Johns Hopkins/Bayview Medical Center
4 The Johns Hopkins University Bloomberg School of Public Health

* To whom correspondence should be addressed. E-mail: phassou1{at}jhmi.edu.

Signaling via p38 MAP kinase has been implicated in the mechanotransduction associated with mechanical stress and ventilator-induced lung injury (VILI). However, the critical downstream mediators of alveolar injury remain incompletely defined. We provide evidence that high tidal volume mechanical ventilation (HVT MV) rapidly activates caspases within the lung resulting in increased alveolar cell apoptosis. Antagonism of MV-induced p38 MAP kinase activity with SB203580 suppresses both MV-induced caspase activity and alveolar apoptosis, placing p38 MAP kinase upstream of MV-induced caspase activation and programmed cell death. The reactive oxygen species (ROS) producing enzyme xanthine oxidoreductase (XOR) is activated in a p38 MAP kinase-dependent manner following HVT MV. Allopurinol, a XOR inhibitor, also suppresses HVT MV-induced apoptosis implicating HVT MV-induced ROS in the induction of alveolar cell apoptosis. Finally, systemic administration of the pan-caspase inhibitor, z-VAD-fmk, but not its inactive peptidyl analog, z-FA-fmk, blocks ventilator-induced apoptosis of alveolar cells and alveolar-capillary leak indicating that caspase-dependent cell death is necessary for VILI-associated barrier dysfunction in vivo.




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