>> High Dose Antithrombin Inhibits HMGB1 and Improves Endotoxin-Induced Acute Lung Injury in Rats
Intensive Care Med. 2007 Oct 17.
Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T.
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasamamachi, 879-5593, Yufu City, Oita, Japan.
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[Symbol: see text]units/kg of ATIII injected into the tail vein.
MEASUREMENTS AND RESULTS: Animals receiving high-dose ATIII (250[Symbol: see text]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[Symbol: see text]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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