title: The emphysematous lung is abnormally sensitive to TRAIL-mediated apoptosis.
abstract: BACKGROUND
  Alveolar apoptosis is increased in the emphysematous lung. However, mechanisms involved are not fully understood. Recently, we demonstrated that levels of TRAIL receptor 1 and 2, levels of p53, and Bax/Bcl-xL ratio were elevated in the lung of subjects with emphysema, despite smoking cessation. Thus, we postulate that due to chronic pulmonary oxidative stress, the emphysematous lung would be abnormally sensitive to TRAIL-mediated apoptosis.
  
  
  METHODS
  A549 cells were exposed to rTRAIL, cigarette smoke extract, and/or H2O2 prior to caspase-3 activity measurement and annexin V staining assessment. In addition, freshly resected lung samples were obtained from non-emphysematous and emphysematous subjects and exposed ex vivo to rTRAIL for up to 18 hours. Lung samples were harvested and levels of active caspase-3 and caspase-8 were measured from tissue lysates.
  
  
  RESULTS
  Both cigarette smoke extract and H2O2 were able to sensitize A549 cells to TRAIL-mediated apoptosis. Moreover, following exposure to rTRAIL, caspase-3 and -8 were activated in lung explants from emphysematous subjects while being decreased in lung explants from non-emphysematous subjects.
  
  
  CONCLUSIONS
  Alveolar sensitivity to TRAIL-mediated apoptosis is strongly increased in the emphysematous lung due to the presence of oxidative stress. This might be a new mechanism leading to increased alveolar apoptosis and persistent alveolar destruction following smoking cessation.
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada.
authors.forename: Mathieu C
authors.initials: MC
authors.lastname: Morissette
authors.forename: Julie
authors.initials: J
authors.lastname: Parent
authors.forename: Julie
authors.initials: J
authors.lastname: Milot
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000368:Aged; D000704:Analysis of Variance; D017304:Annexin A5 / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D017304:Annexin A5; D000975:Antioxidants; D016877:Oxidants; D011994:Recombinant Proteins; D012906:Smoke; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D006861:Hydrogen Peroxide; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D000111:Acetylcysteine