An experimental study of extracellular signal-regulated kinase and its interventional treatments in hepatic fibrosis.
BACKGROUND
The pathogenesis of hepatic fibrosis and cirrhosis is still not fully understood. The extracellular signal-regulated kinase (ERK) pathway is involved in the regulation of cell proliferation and differentiation. The aim of this study was to investigate the effects of PD98059, a specific inhibitor of ERK, on the cell cycle, cell proliferation, secretion of type I collagen and expression of cyclin D1 mRNA, CDK4 mRNA and transforming growth factor-beta1 (TGF-beta1) mRNA in rat hepatic stellate cells (HSCs) stimulated by acetaldehyde.


METHODS
Rat HSCs stimulated by acetaldehyde were incubated with PD98059 at different concentrations. The cell cycle was analysed by flow cytometry. Cell proliferation was assessed by the methyl thiazolyl tetrazolium colorimetric assay. The mRNA expression of cyclin D1, CDK4 and TGF-beta1 was examined using the reverse transcriptase-polymerase chain reaction. Type I collagen in the culture medium was detected by enzyme-linked immunosorbent assay.


RESULTS
20, 50 and 100 micromol/L PD98059 significantly inhibited the proliferation and provoked a G0/G1-phase arrest of acetaldehyde-induced HSCs in a dose-dependent manner. The secretion of type I collagen and the expression of cyclin D1, CDK4 and TGF-beta1 mRNA in acetaldehyde-induced HSCs were markedly inhibited by 50 and 100 micromol/L PD98059, respectively.


CONCLUSIONS
The ERK pathway regulates the cell proliferation, secretion of type I collagen and the expression of TGF-beta1 mRNA in rat HSCs stimulated by acetaldehyde, which is likely related to its regulative effect on the cell cycle.
Jiang
Ming-De
MD
Department of Gastroenterology, General Hospital of Chengdu Military Command, Chengdu 610083, China.
Zheng
Shu-Mei
SM
Xu
Hui
H
Zeng
Wei-Zheng
WZ
Zhang
Yong
Y
Sun
Hao-Ping
HP
Wang
Yun-Xia
YX
Qin
Jian-Ping
JP
Wu
Xiao-Ling
XL
D000079:Acetaldehyde / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D005419:Flavonoids; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D019938:Cyclin D1; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D048049:Extracellular Signal-Regulated MAP Kinases; D000079:Acetaldehyde; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one