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.