Altered factor VII activating protease expression in murine hepatic fibrosis and its influence on hepatic stellate cells.
BACKGROUND
Platelet-derived growth factor-BB (PDGF-BB) is a profibrotic factor in liver fibrosis through its ability to stimulate hepatic stellate cells (HSC). The liver-derived serine protease factor VII activating protease (FSAP) regulates the activities of PDGF-BB in a cell-specific manner.


OBJECTIVE
Our aim was to determine the influence of FSAP on the activation of HSC and to analyse the regulation of FSAP in hepatic fibrogenesis.


METHODS
The effect of FSAP on PDGF-stimulated p42/p44 mitogen-activated protein kinase (MAPK) activation in primary rat HSC was determined by Western blotting. Migration and proliferation of HSC was evaluated in Boyden chamber experiments and (3)H-thymidine incorporation assays respectively. Expression of FSAP was analysed in a CCl(4) mouse model of liver fibrosis by Western blot, quantitative real-time polymerase chain reaction and immunohistochemistry.


RESULTS
FSAP inhibited PDGF-BB-stimulated p42/p44 MAPK phosphorylation, proliferation and migration of HSC. FSAP mRNA expression level was increased 3 h after CCl(4) application and decreased after 18 h and, in established fibrosis, after chronic CCl(4) administration. In parallel, there was a decrease in the circulating FSAP protein in chronic fibrosis. Concurrently, the homogenous hepatic expression pattern of FSAP was disturbed. Immunohistochemistry revealed a decrease of FSAP in hepatocytes in inflammatory and fibrotic lesions.


CONCLUSIONS
Our results demonstrate an inhibitory effect of FSAP on PDGF-mediated activation of HSC. In addition, FSAP expression is transiently increased in acute-phase reaction but decreased during chronic fibrogenesis, which in turn may influence PDGF-BB availability and myofibroblast activity.
Roderfeld
Martin
M
Department of Medicine II, Gastroenterology, Justus-Liebig-University Giessen, Giessen, Germany.
Weiskirchen
Ralf
R
Atanasova
Srebrena
S
Gressner
Axel M
AM
Preissner
Klaus T
KT
Roeb
Elke
E
Kanse
Sandip M
SM
D000818:Animals; D000077214:Becaplermin; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism* / Q000494:pharmacology; D018709:Statistics, Nonparametric
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D020928:Mitogen-Activated Protein Kinases; C433550:HABP2 protein, human; D012697:Serine Endopeptidases