PMID- 29856896
OWN - NLM
STAT- MEDLINE
DCOM- 20190118
LR  - 20190118
IS  - 1365-2559 (Electronic)
IS  - 0309-0167 (Linking)
VI  - 73
IP  - 4
DP  - 2018 Oct
TI  - Extracellular matrix components indicate remodelling activity in different 
      fibrosis stages of human non-alcoholic fatty liver disease.
PG  - 612-621
LID - 10.1111/his.13665 [doi]
AB  - AIMS: The composition of several important extracellular matrix components (ECM) 
      has not yet been elucidated in human non-alcoholic fatty liver disease (NAFLD). 
      We aim to investigate the proportion of hepatic stellate cells (HSCs) and 
      activity of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs 
      (TIMPs) in human NAFLD liver tissue with respect to severity of inflammation and 
      fibrosis. METHODS AND RESULTS: Histopathological features were quantified by 
      NAFLD activity score and grading assignment. The collagen proportionate area 
      (CPA) was measured. Slides were stained with alpha-smooth muscle actin (alpha-SMA), 
      as a marker of activated HSCs, and alpha-SMA was quantified digitally. Zymography was 
      performed to measure the proteolytic activity of MMP-2 and MMP-9. TIMP-1 and 
      TIMP-2 protein concentration was measured with enzyme-linked immunosorbent assay 
      (ELISA). alpha-SMA was higher in severe fibrosis (6.3%, interquartile range 2.9-13.1) 
      than mild and no fibrosis (median 1.1 and 0.9%, P < 0.001) and correlated 
      strongly with CPA (Rs = 0.870, P < 0.001). ProMMP-2 activity in severe (4.1%, IQR 
      2.6-16.2) and mild fibrosis (2.7%, IQR 1.9-3.9) was higher than in no fibrosis 
      (1.5%, (IQR 0.95-2.1); P = 0.001 and P = 0.046) and showed a moderate positive 
      correlation with CPA (Rs = 0.495, P = 0.001). TIMP-1 and TIMP-2 were 
      significantly higher in severe fibrosis than mild or no fibrosis. Both showed 
      moderate correlation with CPA (TIMP-1: Rs = 0.471, P = 0.002 and TIMP-2: Rs = 
      0.325, P = 0.036). MMP-9 correlated as the only ECM component to inflammation 
      severity. CONCLUSIONS: Advanced human NAFLD-fibrosis has a distinct ECM 
      composition with increased HSCs and increased TIMP inhibition, but there is also 
      ongoing remodelling activity of MMP-2.
CI  - (c) 2018 The Authors. Histopathology published by John Wiley & Sons Ltd.
FAU - Munsterman, Isabelle D
AU  - Munsterman ID
AUID- ORCID: 0000-0002-9588-1845
AD  - Department of Gastroenterology and Hepatology, Radboud University Medical Centre, 
      Nijmegen, the Netherlands.
FAU - Kendall, Timothy J
AU  - Kendall TJ
AUID- ORCID: 0000-0002-4174-2786
AD  - Division of Pathology, University of Edinburgh, Edinburgh, UK.
FAU - Khelil, Nawel
AU  - Khelil N
AD  - Department of Gastroenterology and Hepatology, Radboud University Medical Centre, 
      Nijmegen, the Netherlands.
FAU - Popa, Madalina
AU  - Popa M
AD  - Department of Gastroenterology and Hepatology, Radboud University Medical Centre, 
      Nijmegen, the Netherlands.
FAU - Lomme, Roger
AU  - Lomme R
AD  - Laboratory of Experimental Surgery, Radboud University Medical Centre, Nijmegen, 
      the Netherlands.
FAU - Drenth, Joost P H
AU  - Drenth JPH
AD  - Department of Gastroenterology and Hepatology, Radboud University Medical Centre, 
      Nijmegen, the Netherlands.
FAU - Tjwa, Eric T T L
AU  - Tjwa ETTL
AD  - Department of Gastroenterology and Hepatology, Radboud University Medical Centre, 
      Nijmegen, the Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20180713
PL  - England
TA  - Histopathology
JT  - Histopathology
JID - 7704136
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Extracellular Matrix/metabolism/*pathology
MH  - Female
MH  - Hepatic Stellate Cells/metabolism/*pathology
MH  - Humans
MH  - Liver Cirrhosis/etiology/metabolism/*pathology
MH  - Male
MH  - Matrix Metalloproteinases/metabolism
MH  - Middle Aged
MH  - Non-alcoholic Fatty Liver Disease/complications/metabolism/*pathology
MH  - Tissue Inhibitor of Metalloproteinases/metabolism
OTO - NOTNLM
OT  - NAFLD
OT  - extracellular matrix
OT  - histopathology
OT  - human study
OT  - liver fibrosis
EDAT- 2018/06/02 06:00
MHDA- 2019/01/19 06:00
CRDT- 2018/06/02 06:00
PHST- 2018/02/16 00:00 [received]
PHST- 2018/05/30 00:00 [accepted]
PHST- 2018/06/02 06:00 [pubmed]
PHST- 2019/01/19 06:00 [medline]
PHST- 2018/06/02 06:00 [entrez]
AID - 10.1111/his.13665 [doi]
PST - ppublish
SO  - Histopathology. 2018 Oct;73(4):612-621. doi: 10.1111/his.13665. Epub 2018 Jul 13.