PMID- 16336649
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20070724
LR  - 20200929
IS  - 1476-5926 (Electronic)
IS  - 1476-5926 (Linking)
VI  - 4
DP  - 2005 Dec 7
TI  - Regenerative and fibrotic pathways in canine hepatic portosystemic shunt and 
      portal vein hypoplasia, new models for clinical hepatocyte growth factor 
      treatment.
PG  - 7
AB  - BACKGROUND: We analyzed two spontaneous dog diseases characterized by subnormal 
      portal perfusion and reduced liver growth: (i) congenital portosystemic shunts 
      (CPSS) without fibrosis and (ii) primary portal vein hypoplasia (PPVH), a disease 
      associated with fibrosis. These pathologies, that lack inflammation or 
      cholestasis, may represent simplified models to study liver growth and fibrosis. 
      To investigate the possible use of those models for hepatocyte growth factor 
      (HGF) treatment, we studied the functionality of HGF signaling in CPSS and PPVH 
      dogs and compared this to aged-matched healthy controls. RESULTS: We used 
      quantitative real-time polymerase chain reaction (Q-PCR) to analyze the mRNA 
      expression of HGF, transforming growth factor beta1 (TGF-beta1), and relevant 
      mediators in liver biopsies from cases with CPSS or PPVH, in comparison with 
      healthy control dogs. CPSS and PPVH were associated with a decrease in mRNA 
      expression of HGF and of MET proto-oncogene (c-MET). Western blot analysis 
      confirmed the Q-PCR results and showed that intracellular signaling components 
      (protein kinase B/Akt, ERK1/2, and STAT3) were functional. The TGF-beta1 mRNA 
      levels were unchanged in CPSS whereas there was a 2-fold increase in PPVH 
      indicating an active TGF-beta1 pathway, consistent with the observation of 
      fibrosis seen in PPVH. Western blots on TGF-beta1 and phosphorylated Smad2 
      confirmed an activated pro-fibrotic pathway in PPVH. Furthermore, Q-PCR showed an 
      increase in the amount of collagen I present in PPVH compared to CPSS and 
      control, which was confirmed by Western blot analysis. CONCLUSION: The 
      pathophysiological differences between CPSS and PPVH can adequately be explained 
      by the Q-PCR measurements and Western blots. Although c-MET levels were reduced, 
      downstream signaling seemed to be functional and provides a rational for 
      HGF-supplementation in controlled studies with CPSS and PPVH. Furthermore both 
      diseases may serve as simplified models for comparison with more complex chronic 
      inflammatory diseases and cirrhosis.
FAU - Spee, Bart
AU  - Spee B
AD  - Department of Clinical Sciences of Companion Animals, Faculty of Veterinary 
      Medicine, Utrecht University, Utrecht, The Netherlands. b.spee@vet.uu.nl
FAU - Penning, Louis C
AU  - Penning LC
FAU - van den Ingh, Ted S G A M
AU  - van den Ingh TS
FAU - Arends, Brigitte
AU  - Arends B
FAU - Ijzer, Jooske
AU  - Ijzer J
FAU - van Sluijs, Frederik J
AU  - van Sluijs FJ
FAU - Rothuizen, Jan
AU  - Rothuizen J
LA  - eng
PT  - Journal Article
DEP - 20051207
PL  - England
TA  - Comp Hepatol
JT  - Comparative hepatology
JID - 101147643
PMC - PMC1315335
EDAT- 2005/12/13 09:00
MHDA- 2005/12/13 09:01
PMCR- 2005/12/07
CRDT- 2005/12/13 09:00
PHST- 2005/02/10 00:00 [received]
PHST- 2005/12/07 00:00 [accepted]
PHST- 2005/12/13 09:00 [pubmed]
PHST- 2005/12/13 09:01 [medline]
PHST- 2005/12/13 09:00 [entrez]
PHST- 2005/12/07 00:00 [pmc-release]
AID - 1476-5926-4-7 [pii]
AID - 10.1186/1476-5926-4-7 [doi]
PST - epublish
SO  - Comp Hepatol. 2005 Dec 7;4:7. doi: 10.1186/1476-5926-4-7.