Peroxisome proliferator-activated receptor-γ (PPAR- γ), a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors, possesses anti-inflammatory properties. The purpose of the present study was to investigate the profile of PPAR- γ expression in the lung and to explore its functional significance in lipopolysaccharide (LPS)-induced acute lung injury. Thirty male Wistar rats were randomly assigned to one of the following five groups: saline control group and different LPS groups (2 h, 4 h, 6 h and 8 h after LPS 6 mg/kg i.v.). At predefined time points, blood samples were collected to measure plasma level of tumor necrosis factor (TNF)-α and lungs were removed to assay histopathological changes, wet-to-dry weight (W/D) ratio, myeloperoxidase (MPO) activity and TNF-α level. Expression of PPAR- γ and activation of nuclear factor (NF)- κB p65 in lung tissues were also examined in each group. LPS injection resulted in marked lung damage and elevated levels of W/D ratio and MPO activity in the lung. Increased levels of TNF-α were also observed in the plasma and lung. These inflammatory events were associated with reduced expression of PPAR-γ protein and with activation of NF-κB in the lung. Our data suggest that decreased expression of PPAR-γ protein in lungs may contribute to the ongoing pulmonary inflammation and tissue injury in endotoxemia.
Apoptosis of lymphoid tissues during sepsis is well documented and linked to the pathobiology of organ failure and death. In this study, we evaluated the effect of a single dose of recombinant erythropoietin (EPO) on thymic and splenic apoptosis in an endotoxic sepsis model. Young male Wistar rats were divided into 3 groups and administered intraperitoneally (IP) either normal saline; lipopolysaccharide (LPS) 10 mg/kg; or EPO (5000 U/kg) 30 min before lipopolysaccharide. Six hours following LPS administration animals were sacrificed. Apoptosis was assessed by hematoxylin-eosin staining, terminal deoxynucleotide transferase-mediated fluorescein-dUTP nick end labeling (TUNEL), and caspase-3 immunostaining. When compared with animals given LPS, animals pretreated with EPO displayed reduced splenic and thymic TUNEL positivity of 44±3 (p<0.05) and 1434 (p<0.05) nuclei per high power field (hpf), respectively. Caspase-3 positivity was also significantly reduced in the spleen and thymus, with 31±4 (p<0.05) and 93±3 (p<0.05) positive stained nuclei per hpf, respectively. Serum nitrite levels were elevated in animals given lipopolysaccharide. Pretreatment with EPO attenuated the increase in nitrite levels; however, this did not reach statistical significance. We conclude that a single dose of recombinant erythropoietin can reduce thymic and splenic apoptosis associated with lipopolysaccharide administration.