title: PlGF mediates neutrophil elastase-induced airway epithelial cell apoptosis and emphysema.
abstract: BACKGROUND
  Chronic pulmonary obstructive disease (COPD) has become the fourth leading cause of death worldwide. Cigarette smoking induces neutrophil elastase (NE) and contributes to COPD, but the detailed mechanisms involved are not fully established. In an animal model of pulmonary emphysema, there are increased expressions of placenta growth factor (PlGF) and lung epithelial (LE) cell apoptosis. This study hypothesized that excessive NE may up-regulate PlGF and that PlGF-induced LE apoptosis mediates the pathogenesis of pulmonary emphysema.
  
  
  METHODS
  Human bronchial epithelial cells, BEAS-2B, and primary mouse type II alveolar epithelial cells were treated with NE. The PlGF promoter activity was examined by luciferase activity assay, while PlGF expression and secretion were evaluated by RT-PCR, Western blotting, and ELISA. Both cell lines were treated with PlGF to evaluate its effects and the downstream signaling pathways leading to LE cell apoptosis. PlGF knockout and wild-type mice were instilled with NE to determine the roles of PlGF and its downstream molecules in NE-promoted mice pulmonary apoptosis and emphysema phenotype.
  
  
  RESULTS
  The transcriptional factor, early growth response gene-1, was involved in the NE-promoted PlGF promoter activity, and the expression and secretion of PlGF mRNA and protein in LE cells. PlGF-induced LE cell apoptosis and NE-induced mice pulmonary apoptosis and emphysema were mediated by the downstream c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)δ signaling pathways.
  
  
  CONCLUSIONS
  The NE-PlGF-JNK/PKCδ pathway contributes to the pathogenesis of LE cell apoptosis and emphysema. PlGF and its downstream signaling molecules may be potential therapeutic targets for COPD.
authors.affiliation: Departments of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. hohsha@gmail.com.|Department of Internal Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan. hohsha@gmail.com.
authors.forename: Hsin-Han
authors.initials: HH
authors.lastname: Hou
authors.affiliation: Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan. chest5415@hotmail.com.|Department of Chemical Engineering and Materials Science, Yuan-Ze University, Taoyuan, Taiwan. chest5415@hotmail.com.
authors.forename: Shih-Lung
authors.initials: SL
authors.lastname: Cheng
authors.affiliation: Departments of Laboratory Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. gbchung@ntu.edu.tw.
authors.forename: Kuei-Pin
authors.initials: KP
authors.lastname: Chung
authors.affiliation: Departments of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. shuchenwei@ntu.edu.tw.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Wei
authors.affiliation: Departments of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. tsaopn@ntu.edu.tw.
authors.forename: Po-Nien
authors.initials: PN
authors.lastname: Tsao
authors.affiliation: Departments of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. g3911706@gmail.com.|Department of Internal Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan. g3911706@gmail.com.
authors.forename: Hsuan-Hsuan
authors.initials: HH
authors.lastname: Lu
authors.affiliation: Departments of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. haochienwang@gmail.com.|Department of Internal Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan. haochienwang@gmail.com.
authors.forename: Hao-Chien
authors.initials: HC
authors.lastname: Wang
authors.affiliation: Departments of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, Taiwan. jefferycjyu@ntu.edu.tw.|Department of Internal Medicine, National Taiwan University, College of Medicine, Taipei, Taiwan. jefferycjyu@ntu.edu.tw.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051745:Protein Kinase C-delta / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; C497259:Prkcd protein, mouse; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases; D019272:Leukocyte Elastase