Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking.
OBJECTIVE
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 CCl(4) 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.


CONCLUSIONS
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.
Issa
Razao
R
Division of Infection Inflammation and Repair, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
Zhou
Xiaoying
X
Constandinou
Christothea M
CM
Fallowfield
Jonathan
J
Millward-Sadler
Harry
H
Gaca
Marianna D A
MD
Sands
Emma
E
Suliman
Ibnauf
I
Trim
Nathan
N
Knorr
Andreas
A
Arthur
Michael J P
MJ
Benyon
R Christopher
RC
Iredale
John P
JP
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002251:Carbon Tetrachloride; D024042:Collagen Type I / Q000235:genetics; D003432:Cross-Linking Reagents / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012075:Remission, Spontaneous; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics
D000199:Actins; D024042:Collagen Type I; D003432:Cross-Linking Reagents; D004151:Dipeptides; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; C001299:epsilon-(gamma-glutamyl)-lysine; D002251:Carbon Tetrachloride; D020782:Matrix Metalloproteinases