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Leukocyte Elastase Induces Lung Epithelial Apoptosis via a PAR-1–, NF-B–, and p53-Dependent Pathway

¹ Division of Respirology, Department of Medicine, University of Toronto and Toronto General Hospital Research Institute of the University Health Network, Toronto, Ontario, Canada; ² Division of Pulmonary and Critical Care Medicine, Department of Medicine and Pediatrics, National Jewish Health, Denver, Colorado; ³ The Division of Pulmonary Medicine and Critical Care Sciences, Department of Medicine and Integrated Department of Immunology, University of Colorado Denver, Denver, Colorado; and ⁴ Division of Respirology, Department of Medicine, University of Western Ontario, London, Ontario, Canada

Correspondence and requests for reprints should be addressed to Gregory Downey, M.D., K701b, National Jewish Health, 1400 Jackson Street, Denver, CO 80206. E-mail: downeyg{at}njc.org

Leukocyte elastase induces apoptosis of lung epithelial cells via alterations in mitochondrial permeability, but the signaling pathways regulating this response remain uncertain. Here we investigated the involvement of proteinase-activated receptor-1 (PAR-1), the transcription factor NF-B, and the protooncogene p53 in this pathway. Elastase-induced apoptosis of lung epithelial cells correlated temporally with activation of NF-B, phosphorylation, and nuclear translocation of p53, increased p53 up-regulated modulator of apoptosis (PUMA) expression, and mitochondrial translocation of Bax resulting in enhanced permeability. Elastase-induced apoptosis was also prevented by pharmacologic inhibitors of NF-B and p53 and by short interfering RNA knockdown of PAR-1, p53, or PUMA. These inhibitors prevented elastase-induced PUMA expression, mitochondrial translocation of Bax, increased mitochondrial permeability, and attenuated apoptosis. NF-B inhibitors also reduced p53 phosphorylation. We conclude that elastase-induced apoptosis of lung epithelial cells is mediated by a PAR-1–triggered pathway involving activation of NF-B and p53, and a PUMA- and Bax-dependent increase in mitochondrial permeability leading to activation of distal caspases. Further, p53 contributes to elastase-induced apoptosis by both transcriptional and post-transcriptional mechanisms.

Key Words: inflammation • lung injury • neutrophils • proteinase • mitochondria

CLINICAL RELEVANCE These data provide insights into the mechanisms by which leukocyte elastase induces apoptosis of lung epithelia. This has important implications for our understanding of the acute respiratory distress syndrome and emphysema, and provides novel targets for therapeutic intervention.