Gastroenterology

Gastroenterology

Volume 126, Issue 7, June 2004, Pages 1795-1808
Gastroenterology

Basic-alimentary tract
Spontaneous recovery from micronodular cirrhosis: Evidence for incomplete resolution associated with matrix cross-linking

https://doi.org/10.1053/j.gastro.2004.03.009Get rights and content

Abstract

Background & Aims: Liver fibrosis and cirrhosis result from the excessive secretion of matrix proteins by hepatic stellate cells (HSCs). Previously considered irreversible, we have studied a model of cirrhosis to determine the mechanisms mediating and limiting spontaneous recovery. Methods: A micronodular cirrhosis was induced in rats after 12 weeks of CCl4 intoxication. Livers were analyzed for evidence of matrix degradation, matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) expression, stellate cell apoptosis, tissue transglutaminase (tTg) expression, and matrix cross-linking during spontaneous recovery of up to 366 days. Results: Over 366 days of recovery, micronodular cirrhosis underwent significant remodeling to a macronodular cirrhosis. Expression of collagen-1 and TIMP messenger RNA (mRNA) decreased significantly and active MMPs were shown in livers during remodeling of fibrosis. Resolution also was characterized by apoptosis of HSCs, predominantly at the margins of fibrotic septa. Residual septa, not remodeled at 366 days, were characterized by tTg-mediated cross-linking and relative hypocellularity. Conclusion: Recovery from comparatively advanced cirrhosis is possible and results in remodeling from a micronodular cirrhosis to a macronodular cirrhosis. We suggest resolution is limited by tTg-mediated matrix cross-linking and a failure of HSC apoptosis.

Section snippets

Models of advanced fibrosis and cirrhosis

Fibrosis was induced by the twice weekly injection of CCl4 in olive oil vehicle in male Sprague Dawley rats (250–500 g) exactly as previously described in a 4-week CCl4 recovery model.18 The institutional animal care committee and Home Office approved the protocol for animal treatment used in this study. However, in contrast to our previous model, intoxication with CCl4 was continued for periods of 6, 8, and 12 weeks.

Experimental liver fibrosis and macronodular cirrhosis showed evidence of extensive matrix remodeling during spontaneous recovery

All harvested livers in each model were subjected to histologic analysis after picrosirius red and H&E staining and reported blind by H.M.S. as described in the Materials and Methods section. Livers harvested from cohorts of rats treated for 6 weeks with CCl4 (n = 6) showed a septate pattern of fibrosis primarily linking the hepatic (central) veins. One of these 6 livers showed the histologic appearance of an early macronodular cirrhosis. Over a 15- to 28-day recovery period (n = 4–6 at each

Discussion

We have established and characterized a rodent model of 12 weeks of CCl4 treatment, which leads to micronodular cirrhosis. After cessation of CCl4, this micronodular cirrhosis undergoes remodeling to yield a macronodular cirrhosis. The residual macronodular change does not undergo complete remodeling to normal even after a year of recovery. Our data provide evidence that recovery from advanced experimental cirrhosis occurs but is incomplete. By directly comparing the residual septa in this

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    Supported by the Wessex Medical trust and the Children’s Liver Disease Foundation (J.P.I.), the Medical Research Council (MRC) in the form of a Cooperative group grant (G9900297) (J.P.I., R.C.B.), a Wessex Medical Trust “Hope Fellowship” (R.I.), and a grant from Bayer AG (J.P.I., R.C.B.). J.P.I. is a MRC senior clinical fellow.

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