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


METHODS
Prospective study in a university laboratory.


METHODS
We assorted 87 male ApoE knockout mice and 60 wild-type C57/B6 mice randomly into three groups (sepsis, pretreatment, posttreatment).


METHODS
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.


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.
Haraguchi
Go
G
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 113-8519, Tokyo, Japan. goh.cvm@tmd.ac.jp
Kosuge
Hisanori
H
Maejima
Yasuhiro
Y
Suzuki
Jun-Ichi
J
Imai
Takasuke
T
Yoshida
Masayuki
M
Isobe
Mitsuaki
M
D000818:Animals; D001057:Apolipoproteins E / Q000097:blood*; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009195:Peroxidase / Q000378:metabolism; D000077205:Pioglitazone; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D045162:Thiazolidinediones / Q000627:therapeutic use*
D001057:Apolipoproteins E; D016207:Cytokines; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D009195:Peroxidase; D000077205:Pioglitazone