title: Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A.
abstract: Platelet derived growth factor (PDGF) plays a central role in repair mechanisms after acute and chronic tissue damage. To further evaluate the role of PDGF-A in liver fibrogenesis in vivo, we generated transgenic mice with hepatocyte-specific overexpression of PDGF-A using the CRP-gene promoter. Transgenic but not wildtype mice showed expression of PDGF-A mRNA in the liver. Hepatic PDGF-A overexpression was accompanied by a significant increase in hepatic procollagen III mRNA expression as well as TGF-beta1 expression. Liver histology showed increased deposition of extracellular matrix in transgenic but not in wildtype mice. PDGF-A-transgenic mice showed positive sinusoidal staining for alpha-SMA indicating an activation of hepatic stellate cells. Since the profibrogenic effect of PDGF-A was accompanied by increased TGF-beta1 protein concentration in the liver of transgenic mice, it can be postulated that PDGF-A upregulates expression of TGF-beta1 which is a strong activator of hepatic stellate cells. Thus, these results point towards a fibrosis induction by PDGF-A via the TGF-beta1 signalling pathway. In conclusion, expression and functional analysis of PDGF-A in the liver of transgenic mice suggest a relevant profibrogenic role of PDGF-A via TGF-beta1 induction. Counteracting PDGF-A may therefore be one of the effects of tyrosine kinase inhibitors which showed protective effects in animal models of liver fibrosis.
authors.affiliation: 1st Department of Medicine, Johannes-Gutenberg-University, Mainz, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Thieringer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maass
authors.forename: Piotr
authors.initials: P
authors.lastname: Czochra
authors.forename: Borut
authors.initials: B
authors.lastname: Klopcic
authors.forename: Ilka
authors.initials: I
authors.lastname: Conrad
authors.forename: Diana
authors.initials: D
authors.lastname: Friebe
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.forename: Manfred
authors.initials: M
authors.lastname: Blessing
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Andreas
authors.initials: A
authors.lastname: Teufel
authors.forename: Stephan
authors.initials: S
authors.lastname: Kanzler
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D024061:Collagen Type III; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C075278:platelet-derived growth factor A; D002097:C-Reactive Protein