Liver apoptosis is age dependent and is reduced by activation of peroxisome proliferator-activated receptor-gamma in hemorrhagic shock.
A clinical observation in pediatric and adult intensive care units is that the incidence of multiple organ failure in pediatric trauma victims is lower than in adult patients. However, the molecular mechanisms are not yet defined. Recent experimental studies have shown that the nuclear peroxisome proliferator-activated receptor-gamma (PPARgamma) modulates the inflammatory process. In this study, we hypothesized that severity of liver injury may be age dependent and PPARgamma activation may provide beneficial effects. Hemorrhagic shock was induced in anesthetized young (3-5 mo old) and mature male Wistar rats (11-13 mo old) by withdrawing blood to a mean arterial blood pressure of 50 mmHg. After 3 h, rats were rapidly resuscitated with shed blood. Animals were euthanized 3 h after resuscitation. In mature rats, liver injury appeared more pronounced compared with young rats and was characterized by marked hepatocyte apoptosis, extravasation of erythrocytes, and accumulation of neutrophils. The ratio between the antiapoptotic protein Bcl-2 and the proapoptotic protein BAX was lower, whereas activity of caspase-3, the executioner of apoptosis, was higher in liver of mature rats compared with young rats. Plasma alanine aminotransferase levels were not different between the two age groups. This heightened liver apoptosis was associated with a significant downregulation of PPARgamma DNA binding in mature rats compared with young rats. Treatment with the PPARgamma ligand ciglitazone significantly reduced liver apoptosis in mature rats. Our data suggest that liver injury after severe hemorrhage is age dependent and PPARgamma activation is a novel hepatoprotective mechanism.
Zingarelli
Basilia
B
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229, USA. basilia.zingarelli@cchmc.org
Chima
Ranjit
R
O'Connor
Michael
M
Piraino
Giovanna
G
Denenberg
Alvin
A
Hake
Paul W
PW
D000367:Age Factors; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001794:Blood Pressure; D053148:Caspase 3 / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012151:Resuscitation; D012720:Severity of Illness Index; D012771:Shock, Hemorrhagic / Q000378:metabolism* / Q000473:pathology*; D045162:Thiazolidinediones / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494828:Bax protein, rat; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D045162:Thiazolidinediones; D051028:bcl-2-Associated X Protein; D009195:Peroxidase; D000410:Alanine Transaminase; C505410:Casp3 protein, rat; D053148:Caspase 3; C039671:ciglitazone