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Published ahead of print on May 12, 2005, doi:10.1165/rcmb.2005-0109OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 33, pp. 231-247, 2005
© 2005 American Thoracic Society
DOI: 10.1165/rcmb.2005-0109OC

Proteinase-Activated Receptor-1 Mediates Elastase-Induced Apoptosis of Human Lung Epithelial Cells

Tomoko Suzuki, Theo J. Moraes, Eric Vachon, Hedy H. Ginzberg, Tsun-Tsao Huang, Michael A. Matthay, Morley D. Hollenberg, John Marshall, Christopher A. G. McCulloch, Maria Teresa Herrera Abreu, Chung-Wai Chow and Gregory P. Downey

Division of Respirology, Department of Medicine, Department of Surgery, University of Toronto and Toronto General Hospital Research Institute of the University Health Network, and Faculty of Dentistry, CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Ontario; and Department of Pharmacology & Therapeutics, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada; and Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California

Correspondence and requests for reprints should be addressed to Dr. G. P. Downey, Room 6264, Medical Sciences Building, 1 King's College Circle, University of Toronto, Toronto, ON, M5S 1A8 Canada. E-mail: gregory.downey{at}utoronto.ca

Apoptosis of distal lung epithelial cells plays a pivotal role in the pathogenesis of acute lung injury. In this context, proteinases, either circulating or leukocyte-derived, may contribute to epithelial apoptosis and lung injury. We hypothesized that apoptosis of lung epithelial cells induced by leukocyte elastase is mediated via the proteinase activated receptor (PAR)-1. Leukocyte elastase, thrombin, and PAR-1–activating peptide, but not the control peptide, induced apoptosis in human airway and alveolar epithelial cells as assessed by increases in cytoplasmic histone-associated DNA fragments and TUNEL staining. These effects were largely prevented by a specific PAR-1 antagonist and by short interfering RNA directed against PAR-1. To ascertain the mechanism of epithelial apoptosis, we determined that PAR-1AP, thrombin, and leukocyte elastase dissipated mitochondrial membrane potential, induced translocation of cytochrome c to the cytosol, enhanced cleavage of caspase-9 and caspase-3, and led to JNK activation and Akt inhibition. In concert, these observations provide strong evidence that leukocyte elastase mediates apoptosis of human lung epithelial cells through PAR-1–dependent modulation of the intrinsic apoptotic pathway via alterations in mitochondrial permeability and by modulation of JNK and Akt.

Key Words: acute lung injury • proteinases • inflammation • signal transduction




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