title: Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking.
abstract: 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.
authors.affiliation: Division of Infection Inflammation and Repair, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: Razao
authors.initials: R
authors.lastname: Issa
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhou
authors.forename: Christothea M
authors.initials: CM
authors.lastname: Constandinou
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fallowfield
authors.forename: Harry
authors.initials: H
authors.lastname: Millward-Sadler
authors.forename: Marianna D A
authors.initials: MD
authors.lastname: Gaca
authors.forename: Emma
authors.initials: E
authors.lastname: Sands
authors.forename: Ibnauf
authors.initials: I
authors.lastname: Suliman
authors.forename: Nathan
authors.initials: N
authors.lastname: Trim
authors.forename: Andreas
authors.initials: A
authors.lastname: Knorr
authors.forename: Michael J P
authors.initials: MJ
authors.lastname: Arthur
authors.forename: R Christopher
authors.initials: RC
authors.lastname: Benyon
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
mesh_terms: 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
chemical_list: 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