Danaparoid sodium inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats.
BACKGROUND
Systemic inflammatory mediators, including high mobility group box 1 (HMGB1), play an important role in the development of sepsis. Anticoagulants, such as danaparoid sodium (DA), may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesised that DA would act as an inhibitor of systemic inflammation and prevent endotoxin-induced acute lung injury in a rat model.


METHODS
We used male Wistar rats. Animals in the intervention arm received a bolus of 50 U/kg of DA or saline injected into the tail vein after lipopolysaccharide (LPS) administration. We measured cytokine (tumour necrosis factor (TNF)alpha, interleukin (IL)-6 and IL-10) and HMGB1 levels in serum and lung tissue at regular intervals for 12 h following LPS injection. The mouse macrophage cell line RAW 264.7 was assessed following stimulation with LPS alone or concurrently with DA with identification of HMGB1 and other cytokines in the supernatant.


RESULTS
Survival was significantly higher and lung histopathology significantly improved among the DA (50 U/kg) animals compared to the control rats. The serum and lung HMGB1 levels were lower over time among DA-treated animals. In the in vitro study, administration of DA was associated with decreased production of HMGB1. In the cell signalling studies, DA administration inhibited the phosphorylation of IkappaB.


CONCLUSIONS
DA decreases cytokine and HMGB1 levels during LPS-induced inflammation. As a result, DA ameliorated lung pathology and reduces mortality in endotoxin-induced systemic inflammation in a rat model. This effect may be mediated through the inhibition of cytokines and HMGB1.
Hagiwara
Satoshi
S
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Oita, Japan. saku@med.oita-u.ac.jp
Iwasaka
Hideo
H
Hidaka
Seigo
S
Hishiyama
Sohei
S
Noguchi
Takayuki
T
D000818:Animals; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D003871:Dermatan Sulfate / Q000494:pharmacology*; D004731:Endotoxins / Q000633:toxicity; D024243:HMGB1 Protein / Q000378:metabolism; D006497:Heparan Sulfate / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000517:prevention & control*; D015996:Survival Rate; D018746:Systemic Inflammatory Response Syndrome / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D004731:Endotoxins; D024243:HMGB1 Protein; D006497:Heparan Sulfate; D020672:I-kappa B Proteins; D016753:Interleukin-10; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C083487:I kappa B beta protein; C035838:danaparoid