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

• Published in: Journal of applied physiology (1985) 2008-10, Vol.105 (4), p.1282-1290
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Capillary Permeability; Caspase 3 - metabolism; Caspase 7 - metabolism; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Inhibitor drugs; Injuries; Kinases; Lung Diseases - enzymology; Lung Diseases - etiology; Lung Diseases - pathology; Lung Diseases - prevention & control; Lungs; Male; Mice; Mice, Inbred C57BL; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Pulmonary Alveoli - blood supply; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - enzymology; Pulmonary Alveoli - injuries; Pulmonary Alveoli - pathology; Respiration, Artificial - adverse effects; Time Factors; Xanthine Dehydrogenase - antagonists & inhibitors; Xanthine Dehydrogenase - metabolism
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.90689.2008

1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, 2 Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, and 3 Division 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 (HV T 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 HV T MV. Allopurinol, a XOR inhibitor, also suppresses HV T MV-induced apoptosis, implicating HV T 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 Address for reprint requests and other correspondence: P. M. Hassoun, Div. of Pulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (e-mail: phassoun{at}jhmi.edu )