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

Intensive Care Med. 2008 Jul;34(7):1304-12. doi: 10.1007/s00134-008-1024-9. Epub 2008 Feb 19.

Abstract

Objective: To determine whether peroxisome proliferator-activated receptor (PPAR) gamma ligands improve survival of patients with septic shock we treated a mouse model of sepsis [apolipoprotein (Apo) E) knockout mice] with pioglitazone, a PPAR-gamma 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / blood*
  • Cytokines / blood
  • Enzyme-Linked Immunosorbent Assay
  • Hypoglycemic Agents / therapeutic use*
  • Inflammation / drug therapy*
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Lung / drug effects*
  • Lung / enzymology
  • Lung / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Peroxidase / metabolism
  • Pioglitazone
  • Sepsis / drug therapy*
  • Sepsis / metabolism
  • Sepsis / mortality
  • Thiazolidinediones / therapeutic use*

Substances

  • Apolipoproteins E
  • Cytokines
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Peroxidase
  • Pioglitazone