TY - JOUR
T1 - Alveolar cell apoptosis is dependent on p38 MAP kinase-mediated activation of xanthine oxidoreductase in ventilator-induced lung injury
AU - Le, Anne
AU - Damico, Rachel
AU - Damarla, Mahendra
AU - Boueiz, Adel
AU - Hyun, Hae Pae
AU - Skirball, Jarrett
AU - Hasan, Emile
AU - Peng, Xinqi
AU - Chesley, Alan
AU - Crow, Michael T.
AU - Reddy, Sekhar P.
AU - Tuder, Rubin M.
AU - Hassoun, Paul M.
PY - 2008/10
Y1 - 2008/10
N2 - 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.
AB - 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.
KW - Mechanical stress
KW - Pulmonary capillary leakage
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UR - http://www.scopus.com/inward/citedby.url?scp=55449089822&partnerID=8YFLogxK
U2 - 10.1152/japplphysiol.90689.2008
DO - 10.1152/japplphysiol.90689.2008
M3 - Article
C2 - 18669934
AN - SCOPUS:55449089822
SN - 8750-7587
VL - 105
SP - 1282
EP - 1290
JO - Journal of applied physiology
JF - Journal of applied physiology
IS - 4
ER -