PMID- 11093731
OWN - NLM
STAT- MEDLINE
DCOM- 20010104
LR  - 20220410
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 32
IP  - 6
DP  - 2000 Dec
TI  - Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a 
      transgenic mouse model.
PG  - 1248-54
AB  - Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased 
      in liver fibrosis development both in murine experimental models and human 
      samples. However, the direct role of TIMP-1 during liver fibrosis development has 
      not been defined. To address this issue, we developed transgenic mice 
      overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin 
      promoter/ enhancer. A model of CCl(4)-induced hepatic fibrosis was used to assess 
      the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and 
      control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 
      itself did not induce liver fibrosis. There were no significant differences of 
      pro-(alpha1)-collagen-I, (alpha2)-collagen-IV, and alpha-smooth muscle actin 
      (alpha-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, 
      suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate 
      cell (HSC) activation. After 4-week treatment with CCl(4), however, densitometric 
      analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis 
      compared with the Cont-mice. The hepatic hydroxyproline content and serum 
      hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas 
      CCl(4)-induced liver dysfunction was not altered. An active form of matrix 
      metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased 
      relative to that in Cont-mice because of the transgenic TIMP-1. 
      Immunohistochemical analysis revealed that collagen-I and collagen-IV 
      accumulation was markedly increased in the liver of CCl(4)-treated TIMP-Tg-mice 
      with a pattern similar to that of alpha-SMA positive cells. These results suggest 
      that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes 
      liver fibrosis development.
FAU - Yoshiji, H
AU  - Yoshiji H
AD  - Third Department of Internal Medicine, Nara Medical University, Nara, Japan. 
      yoshijih@naramed-u.ac.jp
FAU - Kuriyama, S
AU  - Kuriyama S
FAU - Miyamoto, Y
AU  - Miyamoto Y
FAU - Thorgeirsson, U P
AU  - Thorgeirsson UP
FAU - Gomez, D E
AU  - Gomez DE
FAU - Kawata, M
AU  - Kawata M
FAU - Yoshii, J
AU  - Yoshii J
FAU - Ikenaka, Y
AU  - Ikenaka Y
FAU - Noguchi, R
AU  - Noguchi R
FAU - Tsujinoue, H
AU  - Tsujinoue H
FAU - Nakatani, T
AU  - Nakatani T
FAU - Thorgeirsson, S S
AU  - Thorgeirsson SS
FAU - Fukui, H
AU  - Fukui H
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Actins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 9007-34-5 (Collagen)
RN  - CL2T97X0V0 (Carbon Tetrachloride)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
SB  - IM
MH  - Actins/genetics/metabolism
MH  - Animals
MH  - Carbon Tetrachloride/pharmacology
MH  - Collagen/genetics
MH  - Humans
MH  - Immunohistochemistry
MH  - Liver/drug effects/enzymology/metabolism
MH  - Liver Cirrhosis/*chemically induced
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred CBA
MH  - Mice, Transgenic/genetics
MH  - Muscle, Smooth/metabolism
MH  - RNA, Messenger/metabolism
MH  - Reference Values
MH  - *Tissue Inhibitor of Metalloproteinase-1/genetics
EDAT- 2000/11/28 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/11/28 11:00
PHST- 2000/11/28 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/11/28 11:00 [entrez]
AID - S0270-9139(00)20975-0 [pii]
AID - 10.1053/jhep.2000.20521 [doi]
PST - ppublish
SO  - Hepatology. 2000 Dec;32(6):1248-54. doi: 10.1053/jhep.2000.20521.