EXPRESSION OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA (PPAR??) IS AGEDEPENDENT IN LUNG INJURY DURING HEMORRHAGIC SHOCK

Abstract

A common 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 the adult population. However, the molecular mechanisms are not yet defined. Recently, several in vitro studies have proposed that the nuclear receptor PPARγ may modulate the inflammatory process. We hypothesized that severity of lung injury may be age-dependent and may correlate with changes in PPARγ expression. Hemorrhagic shock was induced in anesthetized young (3-5 months old) and mature male Wistar rats (11-12 months old) by withdrawing blood into a reservoir to a mean arterial blood pressure of 50 mmHg. After 3 h, the animals were rapidly resuscitated by infusing the shed blood. Animals were then sacrificed 3 h after resuscitation. In young rats, lung injury was characterized by extravasation of red cells and accumulation of inflammatory cells. Neutrophil infiltration was confirmed by measurement of myeloperoxidase activity (805±35 U/100 mg tissue). In contrast, the severity of lung injury was more pronounced in mature rats. Myeloperoxidase activity was significantly higher (1177±99 U/100 mg tissue) when compared to young rats (P < 0.05). To further investigate the molecular mechanisms underlying the pronounced injury in mature animals, we evaluated the nuclear expression of PPARγ. By Western blot analysis, we observed that nuclear content of PPARγ in lungs decreased at 3h after hemorrhage, it increased within 1 h after resuscitation and declined progressively thereafter in young rats. Interestingly, the degree of downregulation of this receptor was more pronounced in mature rats when compared with the younger group. Our data suggest that lung injury after severe hemorrhage is age-dependent and may be secondary to a diverse regulation of the PPARγ pathway. (Supported by NIH grant R01 GM-67202).