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Published ahead of print on May 12, 2005, doi:10.1165/rcmb.2005-0109OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 3, September 2005, 231-247

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Submitted on March 18, 2005
Revised on May 12, 2005

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

Tomoko Suzuki1, Theo J Moraes1, Eric Vachon1, Hedy H Ginzberg1, Tsun-Tsao Huang1, Michael A Matthay2, Morley D Hollenberg3, John Marshall4, Christopher A.G. McCulloch5, Maria Teresa Herrera Abreu1, Chung-Wai Chow1, and Gregory P Downey1*

1 Division of Respirology, Department of Medicine, University of Toronto and Toronto General Hospital Research Institute of the University Health Network, Toronto, ON, Canada, 2 Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA, USA, 3 Department of Pharmacology and Therapeutics, University of Calgary, Calgary, AB, Canada, 4 Department of Surgery, University of Toronto and Toronto General Hospital Research Institute of the University Health Network, Toronto, ON, Canada, 5 Faculty of Dentistry/CIHR Group in Matrix Dynamics, Univesity of Toronto, Toronto, ON, Canada

* To whom correspondence should be addressed. 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 (siRNA) 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.




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