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

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Abstract

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.

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Acknowledgements

We thank Michiyo Deushi and Noriko Tamura for excellent technical assistance. We also appreciate Dr. Julie Trudel's kind advice.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan

    Go Haraguchi, Hisanori Kosuge, Yasuhiro Maejima, Jun-Ichi Suzuki & Mitsuaki Isobe

  2. Department of Medical Biochemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan

    Masayuki Yoshida

  3. Division of Intensive Care Unit, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan

    Go Haraguchi & Takasuke Imai

Authors
  1. Go Haraguchi
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  2. Hisanori Kosuge
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  4. Jun-Ichi Suzuki
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  5. Takasuke Imai
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  7. Mitsuaki Isobe
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Corresponding author

Correspondence to Go Haraguchi.

Additional information

This study was supported by grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology.

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Haraguchi, G., Kosuge, H., Maejima, Y. et al. Pioglitazone reduces systematic inflammation and improves mortality in apolipoprotein E knockout mice with sepsis. Intensive Care Med 34, 1304–1312 (2008). https://doi.org/10.1007/s00134-008-1024-9

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  • DOI: https://doi.org/10.1007/s00134-008-1024-9

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