title: Elastase induces lung epithelial cell autophagy through placental growth factor: a new insight of emphysema pathogenesis.
abstract: Chronic obstructive pulmonary disease (COPD) is a devastating disease, which is associated with increasing mortality and morbidity. Therefore, there is a need to clearly define the COPD pathogenic mechanism and to explore effective therapies. Previous studies indicated that cigarette smoke (CS) induces autophagy and apoptosis in lung epithelial (LE) cells. Excessive ELANE/HNE (elastase, neutrophil elastase), a factor involved in protease-antiprotease imbalance and the pathogenesis of COPD, causes LE cell apoptosis and upregulates the expression of several stimulus-responsive genes. However, whether or not elastase induces autophagy in LE cell remains unknown. The level of PGF (placental growth factor) is higher in COPD patients than non-COPD controls. We hypothesize that elastase induces PGF expression and causes autophagy in LE cells. In this study, we demonstrated that porcine pancreatic elastase (PPE) induced PGF expression and secretion in LE cells in vitro and in vivo. The activation of MAPK8/JNK1 (mitogen-activated protein kinase 8) and MAPK14/p38alpha MAPK signaling pathways was involved in the PGF mediated regulation of the TSC (tuberous sclerosis complex) pathway and autophagy in LE cells. Notably, PGF-induced MAPK8 and MAPK14 signaling pathways mediated the inactivation of MTOR (mechanistic target of rapamycin), the upregulation of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β) and the increase of autophagosome formation in mice. Furthermore, the PPE-induced autophagy promotes further apoptosis in vitro and in vivo. In summary, elastase-induced autophagy promotes LE cell apoptosis and pulmonary emphysema through the upregulation of PGF. PGF and its downstream MAPK8 and MAPK14 signaling pathways are potential therapeutic targets for the treatment of emphysema and COPD.
authors.affiliation: Department of Internal Medicine; National Taiwan University Hospital; Taiwan; Department of Internal Medicine; College of Medicine; National Taiwan University; Taiwan.
authors.forename: Hsin-Han
authors.initials: HH
authors.lastname: Hou
authors.affiliation: Department of Internal Medicine; Far Eastern Memorial Hospital; Taiwan; Department of Chemical Engineering and Materials Science; Yuan-Ze University; Taiwan.
authors.forename: Shih-Lung
authors.initials: SL
authors.lastname: Cheng
authors.affiliation: Department of Laboratory Medicine; National Taiwan University Hospital; Taiwan.
authors.forename: Kuei-Pin
authors.initials: KP
authors.lastname: Chung
authors.affiliation: Graduate Institute of Clinical Dentistry; School of Dentistry; National Taiwan University; Taiwan; Department of Dentistry; National Taiwan University Hospital; National Taiwan University; Taiwan.
authors.forename: Mark Yen-Ping
authors.initials: MY
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Clinical Dentistry; School of Dentistry; National Taiwan University; Taiwan; Department of Dentistry; National Taiwan University Hospital; National Taiwan University; Taiwan.
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Oral Biology; School of Dentistry; National Taiwan University; Taiwan.
authors.forename: Bei-En
authors.initials: BE
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine; National Taiwan University Hospital; Taiwan; Department of Internal Medicine; College of Medicine; National Taiwan University; Taiwan.
authors.forename: Hsuan-Hsuan
authors.initials: HH
authors.lastname: Lu
authors.affiliation: Department of Internal Medicine; National Taiwan University Hospital; Taiwan; Department of Internal Medicine; College of Medicine; National Taiwan University; Taiwan.
authors.forename: Hao-Chien
authors.initials: HC
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine; National Taiwan University Hospital; Taiwan; Department of Internal Medicine; College of Medicine; National Taiwan University; Taiwan.
authors.forename: Chong-Jen
authors.initials: CJ
authors.lastname: Yu
mesh_terms: D001343:Autophagy / Q000502:physiology; D002460:Cell Line; D004646:Emphysema / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; D048308:Mitogen-Activated Protein Kinase 14; D048055:Mitogen-Activated Protein Kinase 8; D010196:Pancreatic Elastase
keywords: autophagy; chronic obstructive pulmonary disease; elastase; placental growth factor