title: Hepatic growth factor (HGF) inhibits cigarette smoke extract induced apoptosis in human bronchial epithelial cells.
abstract: Low concentrations of cigarette smoke induced DNA damage and repair without leading to apoptosis in human bronchial epithelial cells. Higher concentrations of cigarette smoke, however, could induce either apoptosis or necrosis. The current study demonstrated that 15% cigarette smoke extract (CSE) induced apoptosis as evidenced by DNA content profiling (17.8±2.1% vs 10.2±1.6% of control, p<0.05), LIVE/DEAD staining (60.2±2.1% viable cells in CSE-treated vs 86.5±2.3% in control cells, p<0.05), and COMET assay (24.3±0.6% of Apoptotic Index in the cells treated with CSE vs 4.7±0.6% of control, P<0.05). Hepatocyte growth factor (HGF) significantly blocked the cigarette smoke-induced apoptosis as shown by DNA profiling (10.8±1.5% of CSE+HGF, p<0.05), LIVE/DEAD staining (78.5±1.2% in CSE+HGF treated cells, p<0.05), and COMET assay (Apoptotic Index: 10.0±0.8% in CSE+HGF treated cells, P<0.05). This protective effect of HGF on CSE-induced apoptosis was abolished by PI3K inhibitors, wortmannin and LY294002, and by introduction of the dominant negative AKT into the cells. Furthermore, CSE plus HGF could induce phosphorylation of AKT Thr 308 and the pro-apoptotic protein, BAD. These results suggest that HGF modulates cell survival in response to cigarette smoke exposure through the PI3K/AKT signaling pathway.
authors.affiliation: Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5910, USA.
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Togo
authors.forename: Hisa
authors.initials: H
authors.lastname: Sugiura
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Xingqi
authors.initials: X
authors.lastname: Wang
authors.forename: Koh
authors.initials: K
authors.lastname: Kamio
authors.forename: Shin
authors.initials: S
authors.lastname: Kawasaki
authors.forename: Peter
authors.initials: P
authors.lastname: Bitterman
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001980:Bronchi / Q000166:cytology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D009336:Necrosis / Q000139:chemically induced; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000737:chemistry*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D020169:Caspases; D004247:DNA; D004791:Enzyme Inhibitors; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012906:Smoke; D051636:X-Linked Inhibitor of Apoptosis Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C494819:BAD protein, human; C494811:BCL2L1 protein, human; C066855:HGF protein, human; C496866:XIAP protein, human