title: Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cells.
abstract: 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.
authors.affiliation: Division of Respirology, Department of Medicine, University of Toronto and Toronto General Hospital Research Institute, 1 King's College Circle, Toronto, Ontario, M5S 1A8 Canada.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Suzuki
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Moraes
authors.forename: Eric
authors.initials: E
authors.lastname: Vachon
authors.forename: Hedy H
authors.initials: HH
authors.lastname: Ginzberg
authors.forename: Tsun-Tsao
authors.initials: TT
authors.lastname: Huang
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: Christopher A G
authors.initials: CA
authors.lastname: McCulloch
authors.forename: Maria Teresa Herrera
authors.initials: MT
authors.lastname: Abreu
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Chow
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019272:Leukocyte Elastase / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D009842:Oligopeptides; C462999:PAR-1-activating peptide; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D019272:Leukocyte Elastase; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases