Hepatic growth factor (HGF) inhibits cigarette smoke extract induced apoptosis in human bronchial epithelial cells.
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.
Togo
Shinsaku
S
Pulmonary, Critical Care, Sleep and Allergy Division, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5910, USA.
Sugiura
Hisa
H
Nelson
Amy
A
Kobayashi
Tetsu
T
Wang
Xingqi
X
Kamio
Koh
K
Kawasaki
Shin
S
Bitterman
Peter
P
Rennard
Stephen I
SI
Liu
Xiangde
X
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
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