Pioglitazone reduces systematic inflammation and improves mortality in apolipoprotein E knockout mice with sepsis

Objective To determine whether peroxisome proliferator-activated receptor (PPAR) γ ligands improve survival of patients with septic shock we treated a mouse model of sepsis [apolipoprotein (Apo) E) knockout mice] with pioglitazone, a PPAR-γ ligand. ApoE knockout mice have a high mortality rate due to sepsis because the endotoxin is not cleared. Design and setting Prospective study in a university laboratory. Subjects We assorted 87 male ApoE knockout mice and 60 wild-type C57/B6 mice randomly into three groups (sepsis, pretreatment, posttreatment). Interventions Cecal ligation and puncture (CLP) was carried out in the sepsis and treatment groups. Mice were injected with pioglitazone (5 mg/kg per day) on the day before CLP or 6 h after surgery. Measurements and results Both pre- and post-CLP treatment with pioglitazone improved survival of ApoE knockout and wild-type mice. Serum levels of cytokines and chemokines and myeloperoxidase activity in lung and liver were suppressed in the pioglitazone-treated group. Pioglitazone also suppressed monocyte adhesion to vascular endothelium under flow conditions. Conclusions Pioglitazone improved survival of ApoE knockout mice after onset of septic shock through suppression of inflammatory responses.