PMID- 9401768
OWN - NLM
STAT- MEDLINE
DCOM- 19980223
LR  - 20131121
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 122
IP  - 6
DP  - 1997 Nov
TI  - Effect of pentoxifylline on the degradation of procollagen type I produced by 
      human hepatic stellate cells in response to transforming growth factor-beta 1.
PG  - 1047-54
AB  - 1. Pentoxifylline (PTF) may act as a potential antifibrogenic agent by inhibiting 
      cell proliferation and/or collagen deposition in cell type(s) responsible for the 
      accumulation of extracellular matrix. The aim of the present study was to 
      investigate at which level PTF may affect synthesis and degradation of type I 
      collagen in human hepatic stellate cells (HSCs), a key source of connective 
      tissue in fibrotic liver. 2. Procollagen type I synthesis and release were 
      evaluated in cells maintained in serum free/insulin free medium for 48 h and then 
      stimulated with transforming growth factor-beta 1 (TGF-beta 1) for different time 
      periods in the presence or absence of PTF. TGF-beta 1 caused an upregulation of 
      procollagen I mRNA levels with a peak increase after 3-6 h of stimulation. This 
      effect was followed by an increase in both the cell associated and the 
      extracellular levels of the corresponding protein, with a peak effect at 9-12 h 
      after the addition of TGF-beta 1. Co-incubation with PTF slightly but 
      consistently reduced basal as well as stimulated procollagen I mRNA levels, with 
      negligible effects on the cell-associated expression of the corresponding 
      protein. Conversely, PTF dose-dependently reduced procollagen type I levels 
      detected in supernatants from unstimulated and stimulated cells. 3. Pulse-chase 
      experiments employing L-[3H]-proline revealed that PTF was able to induce 
      significantly the degradation of procollagen, mainly in the extracellular 
      compartment. We next analysed the effect of PTF on the major pathway involved in 
      type I collagen degradation. PTF did not affect the expression of 
      metalloproteinase 1 (MMP-1) mRNA both in basal and stimulated conditions, whereas 
      it markedly reduced the expression of tissue inhibitor of metalloproteinase 1 
      (TIMP-1) mRNA. Accordingly incubation with PTF increased the levels of 'activated 
      MMP-1' in cell supernatants in both basal and stimulated conditions. 4. These 
      results suggest that the antifibrogenic action of PTF on human HSCs is mainly 
      mediated by extracellular collagen degradation rather than by a reduction of 
      collagen synthesis.
FAU - Romanelli, R G
AU  - Romanelli RG
AD  - Istituto di Medicina Interna-Centro Interuniversitario di Fisiopatologia Epatica, 
      Universita di Firenze, Italy.
FAU - Caligiuri, A
AU  - Caligiuri A
FAU - Carloni, V
AU  - Carloni V
FAU - DeFranco, R
AU  - DeFranco R
FAU - Montalto, P
AU  - Montalto P
FAU - Ceni, E
AU  - Ceni E
FAU - Casini, A
AU  - Casini A
FAU - Gentilini, P
AU  - Gentilini P
FAU - Pinzani, M
AU  - Pinzani M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Procollagen)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 76057-06-2 (Transforming Growth Factors)
RN  - EC 3.4.24.- (Collagenases)
RN  - EC 3.4.24.7 (Matrix Metalloproteinase 1)
RN  - SD6QCT3TSU (Pentoxifylline)
SB  - IM
MH  - Cells, Cultured
MH  - Collagenases/genetics
MH  - Extracellular Space/metabolism
MH  - Humans
MH  - Hydrolysis
MH  - Liver/cytology/*drug effects/metabolism
MH  - Matrix Metalloproteinase 1
MH  - Pentoxifylline/*pharmacology
MH  - Procollagen/genetics/*metabolism
MH  - RNA, Messenger/genetics
MH  - Tissue Inhibitor of Metalloproteinase-1/genetics
MH  - Transforming Growth Factors/*pharmacology
PMC - PMC1565043
EDAT- 1997/12/24 00:00
MHDA- 1997/12/24 00:01
PMCR- 1998/11/13
CRDT- 1997/12/24 00:00
PHST- 1997/12/24 00:00 [pubmed]
PHST- 1997/12/24 00:01 [medline]
PHST- 1997/12/24 00:00 [entrez]
PHST- 1998/11/13 00:00 [pmc-release]
AID - 0701484 [pii]
AID - 10.1038/sj.bjp.0701484 [doi]
PST - ppublish
SO  - Br J Pharmacol. 1997 Nov;122(6):1047-54. doi: 10.1038/sj.bjp.0701484.