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Alveolar cell apoptosis is dependent on p38 MAP kinase-mediated activation of xanthine oxidoreductase in ventilator-induced lung injury

¹Division of Pulmonary and Critical Care Medicine, Department of Medicine, ²Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, and ³Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 27 May 2008 ; accepted in final form 29 July 2008

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 SB-203580 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.

mechanical stress; pulmonary capillary leakage

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