title: Activation of HGF/c-Met signaling by ultrafine carbon particles and its contribution to alveolar type II cell proliferation.
abstract: Hepatocyte growth factor (HGF) is a potent mitogen and motogen for various epithelial cells. The present study aimed to explore the role of HGF and c-Met receptor in ultrafine carbon particle-induced alveolar type II epithelial (type II) cell proliferation. ICR mice were intratracheally instilled with 100 μg ultrafine carbon black (ufCB) and killed at 21, 48, and 72 days postexposure to examine type II cell proliferation, HGF release, and c-Met activation. In vivo and in vitro applications of neutralizing anti-HGF antibody were used to investigate the causal role of HGF in cell proliferation. The Met kinase inhibitor SU11274 and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 were used to delineate the involvement of c-Met/ERK1/2 in rat L2 pulmonary epithelial cell proliferation. The results demonstrated that in vivo exposure to 100 μg ufCB caused increased HGF in bronchoalveolar lavage fluid, as well as increased HGF production, c-Met phosphorylation, and cell proliferation in type II cells. In vitro study revealed that ufCB caused a dose-dependent increase in HGF release, c-Met phosphorylation, and cell proliferation. Importantly, treatment with the neutralizing anti-HGF antibody significantly blocked ufCB-induced in vivo and in vitro type II cell proliferation. Moreover, SU11274 and PD98059 significantly reduced ufCB-increased L2 cell proliferation. Results from Western blotting demonstrated that SU11274 successfully suppressed ufCB-induced phosphorylation of c-Met and ERK1/2. In summary, the activation of HGF/c-Met signaling is a major pathway involved in ufCB-induced type II cell proliferation.
authors.affiliation: Department of Environmental and Occupational Health, Medical College, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chih-Ching
authors.initials: CC
authors.lastname: Chang
authors.forename: Jia-Jhen
authors.initials: JJ
authors.lastname: Chiu
authors.forename: Shan-Ling
authors.initials: SL
authors.lastname: Chen
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Huang
authors.forename: Hui-Fen
authors.initials: HF
authors.lastname: Chiu
authors.forename: Bo-Huei
authors.initials: BH
authors.lastname: Lin
authors.forename: Chun-Yuh
authors.initials: CY
authors.lastname: Yang
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D052638:Particulate Matter / Q000633:toxicity*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053260:Soot / Q000633:toxicity*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D005419:Flavonoids; D007211:Indoles; D052638:Particulate Matter; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D053260:Soot; D013449:Sulfonamides; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one