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

作者：Le Anne; Damico Rachel; Damarla Mahendra; Boueiz Adel; Pae Hyun Hae; Skirball Jarrett; Hasan Emile; Peng Xinqi; Chesley Alan; Crow Michael T; Reddy Sekhar P; Tuder Rubin M; Hassoun Paul M^*

来源：Journal of Applied Physiology, 2008, 105(4): 1282-1290.

DOI：10.1152/japplphysiol.90689.2008

• mechanical stress
• pulmonary capillary leakage

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.

• 出版日期2008-10