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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.

SUBMITTER: Suzuki T 

PROVIDER: S-EPMC2715314 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Proteinase-activated receptor-1 mediates elastase-induced apoptosis of human lung epithelial cells.

Suzuki Tomoko T   Moraes Theo J TJ   Vachon Eric E   Ginzberg Hedy H HH   Huang Tsun-Tsao TT   Matthay Michael A MA   Hollenberg Morley D MD   Marshall John J   McCulloch Christopher A G CA   Abreu Maria Teresa Herrera MT   Chow Chung-Wai CW   Downey Gregory P GP  

American journal of respiratory cell and molecular biology 20050512 3


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  ...[more]

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