Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats.
Sepsis is the leading cause of death in surgical intensive care units. Although both mild sepsis secondary to cecal ligation and single puncture (CLP) and fulminant, double puncture CLP (2CLP) may provoke hepatocyte death, we hypothesize that regeneration compensates for cell death after CLP but not 2CLP. In male Sprague-Dawley rats, hepatic necrosis, as determined by serum alpha-glutathione S-transferase (alpha-GST) levels, was significantly but equally elevated over time after both CLP and 2CLP. Apoptosis, evaluated using both terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and morphological examination, was minimal after both CLP and 2CLP. Regeneration, assayed by staining tissue for incorporation of exogenously administered bromodeoxyuridine, was present after CLP but not after 2CLP. To further substantiate impaired regeneration, steady-state levels of mRNAs encoding JunB, LRF-1, and cyclin D1 were determined. After 2CLP, the absence of JunB, LRF-1, and cyclin D1 mRNAs confirmed failed activation of the mitogen-activated protein kinase-linked proliferative pathway and progression through the cell cycle. Therefore, failed hepatocyte regeneration may be a manifestation of hepatic dysfunction in fulminant sepsis.
Weiss
Y G
YG
Department of Anesthesia, University of Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA.
Bellin
L
L
Kim
P K
PK
Andrejko
K M
KM
Haaxma
C A
CA
Raj
N
N
Furth
E E
EE
Deutschman
C S
CS
D051700:Activating Transcription Factor 3; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000032:analysis; D002432:Cecum; D019938:Cyclin D1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005982:Glutathione Transferase / Q000097:blood; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration; D008297:Male; D009336:Necrosis; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000503:physiopathology*; D013997:Time Factors; D014158:Transcription, Genetic
D051700:Activating Transcription Factor 3; D015415:Biomarkers; D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D019938:Cyclin D1; C068616:liver regeneration factor 1; D005982:Glutathione Transferase