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Intensive Care Medicine

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01-02-2008 | Experimental

High dose antithrombin III inhibits HMGB1 and improves endotoxin-induced acute lung injury in rats

Authors: Satoshi Hagiwara, Hideo Iwasaka, Shigekiyo Matsumoto, Takayuki Noguchi

Published in: Intensive Care Medicine | Issue 2/2008

Abstract

Objective

High mobility group box 1 (HMGB1) is an important factor in the development of sepsis. Previous work suggests that antithrombin III (ATIII) inhibits inflammation, but the mechanism of action is still poorly understood.

Design and setting

Prospective controlled animal study in a university laboratory.

Materials

Rats were randomly divided into a lipopolysaccharide (LPS)-induced sepsis control group and an ATIII-treated experimental group. Animals in the experimental group received a bolus of 250 units/kg of ATIII injected into the tail vein.

Measurements and results

Animals receiving high-dose ATIII (250 units/kg) had significantly improved lung histopathology and survival compared to the control rats. We measured serum and lung levels of various cytokines and HMGB1 at regular intervals from 0 to 12 h after the induction of sepsis and demonstrated lower HMGB1 levels over time in ATIII-treated animals. In an in vitro experiment, we stimulated the mouse macrophage cell line RAW 264.7 with LPS in the presence or absence of ATIII. Subsequent measurement of HMGB1 concentrations in the supernatant and cell signaling molecules in cell lysates revealed an ATIII dose-dependent decrease in HMGB1 release. Furthermore, inhibition of IkB and p42 phosphorylation was observed with the administration of ATIII, suggestive of downstream signaling pathways.

Conclusions

High-dose ATIII decreases lung pathology and reduces mortality in a rat sepsis model. This finding may be mediated by the inhibition of HMGB1.

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Title: High dose antithrombin III inhibits HMGB1 and improves endotoxin-induced acute lung injury in rats
Authors: Satoshi Hagiwara
Hideo Iwasaka
Shigekiyo Matsumoto
Takayuki Noguchi
Publication date: 01-02-2008
Publisher: Springer-Verlag
Published in: Intensive Care Medicine / Issue 2/2008
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-007-0887-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

High dose antithrombin III inhibits HMGB1 and improves endotoxin-induced acute lung injury in rats

Abstract

Objective

Design and setting

Materials

Measurements and results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Design and setting

Materials

Measurements and results

Conclusions

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