Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. (original) (raw)

Research Article Free access | 10.1172/JCI1018

R C Benyon, J Pickering, M McCullen, M Northrop, S Pawley, C Hovell, and M J Arthur

University Medicine, University of Southampton, Hampshire SO16 6YD, United Kingdom.

Find articles by Iredale, J. in:[JCI](/search/results?q=author.first%5Fname%3A%22J P%22+author.last%5Fname%3A%22Iredale%22&search%5Ftype=advanced) |PubMed |Google Scholar

University Medicine, University of Southampton, Hampshire SO16 6YD, United Kingdom.

Find articles by Benyon, R. in:[JCI](/search/results?q=author.first%5Fname%3A%22R C%22+author.last%5Fname%3A%22Benyon%22&search%5Ftype=advanced) |PubMed |Google Scholar

University Medicine, University of Southampton, Hampshire SO16 6YD, United Kingdom.

Find articles by Pickering, J. in:JCI |PubMed |Google Scholar

University Medicine, University of Southampton, Hampshire SO16 6YD, United Kingdom.

Find articles by McCullen, M. in:JCI |PubMed |Google Scholar

University Medicine, University of Southampton, Hampshire SO16 6YD, United Kingdom.

Find articles by Northrop, M. in:JCI |PubMed |Google Scholar

University Medicine, University of Southampton, Hampshire SO16 6YD, United Kingdom.

Find articles by Pawley, S. in:JCI |PubMed |Google Scholar

University Medicine, University of Southampton, Hampshire SO16 6YD, United Kingdom.

Find articles by Hovell, C. in:JCI |PubMed |Google Scholar

University Medicine, University of Southampton, Hampshire SO16 6YD, United Kingdom.

Find articles by Arthur, M. in:[JCI](/search/results?q=author.first%5Fname%3A%22M J%22+author.last%5Fname%3A%22Arthur%22&search%5Ftype=advanced) |PubMed |Google Scholar

Published August 1, 1998 -More info

Published August 1, 1998 -Version history

View PDF

Abstract

Liver fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSC), which proliferate during fibrotic liver injury. We have studied a model of spontaneous recovery from liver fibrosis to determine the biological mechanisms mediating resolution. Livers were harvested from rats at 0, 3, 7, and 28 d of spontaneous recovery from liver fibrosis induced by 4 wk of twice weekly intraperitoneal injections with CCl4. Hydroxyproline analysis and histology of liver sections indicated that the advanced septal fibrosis observed at time 0 (peak fibrosis) was remodeled over 28 d of recovery to levels close to control (untreated liver). alpha-Smooth muscle actin staining of liver sections demonstrated a 12-fold reduction in the number of activated HSC over the same time period with evidence of HSC apoptosis. Ribonuclease protection analysis of liver RNA extracted at each recovery time point demonstrated a rapid decrease in expression of the collagenase inhibitors TIMP-1 and TIMP-2, whereas collagenase mRNA expression remained at levels comparable to peak fibrosis. Collagenase activity in liver homogenates increased through recovery. We suggest that apoptosis of activated HSC may vitally contribute to resolution of fibrosis by acting as a mechanism for removing the cell population responsible for both producing fibrotic neomatrix and protecting this matrix from degradation via their production of TIMPs.

Version history