Basic-alimentary tractSpontaneous recovery from micronodular cirrhosis: Evidence for incomplete resolution associated with matrix cross-linking☆
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.